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Article

Comparative Analysis of the Structure and Pharmacological Properties of Some Piperidines and Host–Guest Complexes of β-Cyclodextrin

1
South Kazakhstan Medical Academy, 1 Al-Farabi Square, Shymkent 160019, Kazakhstan
2
A.B. Bekturov Institute of Chemical Sciences, 106 Ualikhanov St., Almaty 050010, Kazakhstan
3
Faculty of Chemistry, Kuban State University, Krasnodar 350040, Russia
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(5), 1098; https://doi.org/10.3390/molecules29051098
Submission received: 16 February 2024 / Accepted: 25 February 2024 / Published: 29 February 2024

Abstract

:
Pain and anesthesia are a problem for all physicians. Scientists from different countries are constantly searching for new anesthetic agents and methods of general anesthesia. In anesthesiology, the role and importance of local anesthesia always remain topical. In the present work, a comparative analysis of the results of pharmacological studies on models of the conduction and terminal anesthesia, as well as acute toxicity studies of the inclusion complex of 1-methyl-4-ethynyl-4-hydroxypiperidine (MEP) with β-cyclodextrin, was carried out. A virtual screening and comparative analysis of pharmacological activity were also performed on a number of the prepared piperidine derivatives and their host–guest complexes of β-cyclodextrin to identify the structure–activity relationship. Various programs were used to study biological activity in silico. For comparative analysis of chemical and pharmacological properties, data from previous works were used. For some piperidine derivatives, new dosage forms were prepared as beta-cyclodextrin host–guest complexes. Some compounds were recognized as promising local anesthetics. Pharmacological studies have shown that KFCD-7 is more active than reference drugs in terms of local anesthetic activity and acute toxicity but is less active than host–guest complexes, based on other piperidines. This fact is in good agreement with the predicted results of biological activity.

1. Introduction

Local anesthetics are currently used in almost all areas of practical medicine [1]. The interest in local anesthetics is due to the negative side effects of general anesthesia on the cardiovascular system, central nervous system, gastrointestinal tract, and individual organs. Although a large number of local anesthetic drugs are known, a rather limited number of drugs are used in practice [2].
This is due to the fact that most local anesthetics do not correspond to modern standards and requirements [3]. Thus, they must have a short latent period, a long period of action and high activity, and be non-irritating and low-toxic.
One of the most rational drug design approaches towards pharmacologically active molecules is based on the structural modification of compounds with reported high activity. As we can see from the papers [4,5], some 1-alkoxyalkyl-4-hydroxypiperidine hydrochlorides and previously reported 1-ethoxyethyl analogs have revealed local anesthetic effects [6]. At the same time, as reported previously, the corresponding benzoates were found to be the strongest local anesthetics [7].
It is a well-known fact that there is no clear correlation between the chemical structure of a drug and its biological effects [1]. Thus, minor changes in the structure of a molecule may lead to a complete disappearance or a strong change in the biological activity (e.g., methyl and ethyl alcohol). Modern pharmaceutical research and development is a high-risk investment that typically faces setbacks at various stages of drug development [8]. Because of that, a molecular design based on the use of prediction software has attracted so much attention in recent years [9]. The structure–activity relationship analysis of the known drugs can help predict the chemical structure of new molecules with the desired properties [8].
One of the main reasons for failure in drug research and development is the lack of efficacy and safety, which are substantially correlated with absorption, distribution, metabolism, and excretion (ADME), as well as with toxicity (T) [10]. Therefore, a rapid evaluation of the ADMET parameters is necessary to minimize failures in the drug discovery process. The ADME parameters [11,12] cover pharmacokinetics, which determine whether the intended drug molecule will reach the target protein in the body and how long it will remain in the bloodstream.
Cyclodextrins are widely used in the pharmaceutical industry for transporting and modification of an active substance [13,14]. The formation of inclusion complexes makes it possible to change the properties of the biologically active component in the desired direction, i.e., to increase the bioavailability and resistance to hydrolysis, solubility, and biodegradability of many active substances [15,16]. In order to improve the anesthetic effects and reduce the toxicity of the water-soluble salt forms of piperidine derivatives, we synthesized and studied [7,17,18,19,20,21] the host–guest complexes of some of these compounds with β-cyclodextrin.
In this work, a pharmacological study of terminal anesthesia was conducted, and the acute toxicity of the 1-methyl-4-ethynyl-4-hydroxypiperidin (MEP) inclusion complex with β-cyclodextrin was analyzed. Virtual screening of the pharmacological activity for a number of piperidine derivatives was carried out in order to identify the structure–activity relationship. The results of the virtual screening were compared with their actual pharmacological effects.

2. Results and Discussion

To determine the structure–activity relationship, we used piperidines of the general formula, shown in Figure 1.
Figure 1. The study compounds (R1 = C≡CH, C≡CH=CH2, C≡CPh; R2 = OCOCH3, OCOC2H5, OCOPh; R3 = CH3, C2H4OC2H5, C3H6OC4H9) (see Table 1).
Figure 1. The study compounds (R1 = C≡CH, C≡CH=CH2, C≡CPh; R2 = OCOCH3, OCOC2H5, OCOPh; R3 = CH3, C2H4OC2H5, C3H6OC4H9) (see Table 1).
Molecules 29 01098 g001

2.1. In Silico Pharmacology

In drug development, efficient target binding is not only important, but it also ensures oral bioavailability and drug-like properties. In this regard, the study of the physicochemical properties of compounds is crucial for drug development.
The predictive analysis and in silico studies of possible targets, ADME parameters (absorption, distribution, metabolism, and excretion), and compliance with the bioavailability criteria [11,22] were carried out for the studied compounds.
An analysis of the structures for compliance with Lipinski’s rule of five (molecular weights (MW) ≤ 500, cLogP ≤ 5.0, TPSA ≤ 140 Å2, number of H-acceptors ≤ 10, H-donors ≤ 5) [23,24] was performed, using the SwissADME software package [25]. Compliance with Lipinski’s rule makes the compounds active drug candidates. The substance is unlikely to become an active drug candidate if Lipinski’s rule is violated even by one parameter.
The analysis of lipophilicity (LogP) is provided in Table 2. Optimal values for LogP (P is the partition coefficient of all forms of the molecule between n-octanol and water) are between 0 and 3. LogP < 0 corresponds to the bad permeability of the lipid bilayer; LogP > 3 indicates poor water solubility [26]. Compounds with high cLogP values may have difficulty in achieving the therapeutic targets due to their lipophilicity, which potentially limits their effectiveness.
The LogP value shows moderately good (0.33) absorption and permeability for the MEP. For EEHP and MEBP, the cLogP values are 1.07 and 2.42, respectively. For the other compounds, the distribution coefficient is significantly higher and ranges from 3.30 to 4.93. More positive cLogP values usually indicate a higher concentration of the compound in the lipid phase.
LogS values (logarithm of water solubility value, expressed in log mol/L) above −4 logmol/L and below 10 µg/mL indicate low solubility. In the range of 10–60 μg/mL, the compounds have moderate solubility. All LogS values higher than 60 µg/mL indicate high solubility [27].
The TPSA parameter for EEHP, MEBP, and MEP has a low value of 23.47 Å2 and meets the criteria for oral bioavailability. The MEP compound meets the Lipinski, Egan, and Weber criteria. The Egan filter (Pharmacia filter) is based on the LogP and TPSA parameters. It anticipates drug absorption, depending on the processes involved in the membrane permeability of a small molecule, and considers the molecule drug-like if it has WLOGP ≤ 5.88 and TPSA ≤ 131.6, respectively [28]. The Muegge filter (the Bayer filter) is the independent pharmacophore point filter that separates drug-like and non-drug-like molecules. The Ghose filter (Amgen) describes small molecules based on their physicochemical properties and the existence of functional groups and substructures [28]. EEHP only fails to meet the Muegge criteria due to its low molecular weight. BBB·HCl has failed to meet the Ghose criteria because the calculation was carried out for a hydrochloride form. The remaining compounds correspond to all the criteria provided in Table 3.
All compounds have shown favorable bioavailability values (0.55). This indicates good suitability for oral drug administration and implies achieving a therapeutic result at lower concentrations.
The radar diagrams (Figure 2) show the distribution of the physicochemical properties of the compounds: lipophilicity (LIPO), size (SIZE), polarity (POLAR), solubility (INSOLU), saturation (INSATU), elasticity (FLEX), presence of donors (nHD), and proton acceptors (nHA). The pink area represents the optimal range for each property (lipophilicity: XLOGP3 −0.7 to +5.0, size: molecular weight 150 to 500 g/mol, polarity: TPSA 20 to 130 Å2, solubility: log S not above 6, saturation: the fraction of carbons in sp3 hybridization is at least 0.25 and flexibility no more than nine rotating bonds) [25]. The analyses of the diagrams show that prosidol, kazcaine, and AEPP have the best distribution of parameters, though all the compounds, in principle, meet the requirements for a medicinal substance. BVBP and BBB have a slight excess in the FLEX parameter, and for MEP, the size, polarity, and flexibility indicators are at the lower limit.
To predict possible biological effects, the open software products PASS Online, AntiBac-Pred, and AntiFun Pred [29,30,31] were used. Here, and below, the score function F = Pa − Pi is used, which is the difference in the probabilities that a substance will be active (Pa) or inactive (Pi) for the corresponding biological activity.
In Table 4, the results for MEP are provided (for F > 0.1). Based on these data, the most probable biological activity of MEP is the suppression of ovulation; there is also a very high probability of its influence on the hormones responsible for reproductive functions. The substance can be used as an anticonvulsant. The other activities (anesthetic, anabolic, nootropic, antidepressant, analgesic, and muscle relaxant) have a rather low probability. Comparative data on the major types of activity for all the substances under consideration are provided in Table 5. The results are provided for the substances in the form of bases since the calculation programs, in most cases, cannot work with the substances in the form of salts and complex compounds (including inclusion complexes).
Possible protein targets (for Homo sapiens) were evaluated using the Swiss Target Prediction service. The results are shown in Table 6. The score for each target is called “confidence”, which is the difference between probabilities of chemical compounds interacting and not interacting with a particular target. Higher confidence means a higher chance of a positive prediction being true. The first 5–6 results are listed and the rest are provided in the Supplementary Materials. The probabilities for MEP are very low, but we can conclude that the substance may affect mechanisms that occur in the central nervous system.
The PASS Targets program provides a slightly different prediction of possible molecular targets. It is advisable to consider results with a confidence value greater than 0.5. Table 7 shows the values greater than 0.5 for MEP, EEHP, and MEBP and greater than 0.25 for the remaining compounds. The full list is presented in Table S1.
According to Table 7, MEP has the largest number of possible targets with a confidence value greater than 0.5. It looks most similar to kazcaine according to the list of possible targets, though the character of the data obtained (a large number of targets and high probability values) should rather be considered an anomaly. The substances MEP, EEHP, and MEBP actively bind to protein kinases.
In silico prediction of acute toxicity values (LD50) for rats for four types of administration (oral, intravenous, intraperitoneal, subcutaneous, and inhalation) was carried out using the GUSAR program [32]. This program compares the structure of a substance with structures from the SYMYX MDL toxicity database. In order to assess which of these drugs best corresponds to the optimal characteristics required for an ideal drug, the acute toxicity parameter LD50 (known as the “lethal dose, 50%” or oral acute dose for rats) was calculated. High toxicity was indicated by values of 1–50 mg/kg; average toxicity was in the range of 51–500 mg/kg. Low toxicity values were 501–5000 mg/kg [33]. The GUSAR program could not calculate data for BBB HCl in the form of either hydrochloride (which is expected) or a base.
The acute toxic class is provided according to the OECD. Low concentrations of the substance reduce the risk of side effects and toxicity. Analyzing the data in Table 8, it can be argued that the acute toxicity values of the compounds exceed the values of the average toxicity range for the compounds prosidol, AEPP, and BVBP. MEP showed a fairly low predicted toxicity risk for intraperitoneal, intravenous, and subcutaneous administration but higher toxicity for all routes of administration compared to the other study drugs.
The prognosis of adverse effects (arrhythmia, heart failure, hepatotoxicity, myocardial infarction, and nephrotoxicity) was made using ADVER Pred [34]. The results are shown in Table 9 and Figure 3.
The compounds may exhibit side effects such as arrhythmia (prosidol, kazcaine, AEPP, BVBP, and BBB), hepatotoxicity (MEP, kazcaine, AEPP, EEHP, and MEBP), myocardial infarction (kazkain and MEBP), and nephrotoxicity (MEBP and EEHP). Kazcaine was predicted to cause the highest number of adverse effects compared to the other compounds. However, their probability, excluding hepatotoxicity, was low. The calculated results also indicate a high probability of hepatotoxicity for MEP. For most compounds, a high probability of arrhythmia was predicted as an adverse effect. In order to improve the bioavailability parameters and reduce the toxic side effects, it is advisable to use active compounds in the form of inclusion complexes with cyclodextrin.

2.2. Host–Guest Complexes with β-Cyclodextrin

The severity of adverse effects, such as hepatotoxicity and nephrotoxicity, can be reduced using drug inclusion complexes with β-cyclodextrin. Cyclodextrins usually improve the solubility of guest molecules in water, significantly reduce their toxicity, and increase the period of action due to the slow dissociation of the inclusion complex in the body.
Usually, the drugs are used not in a pure form but in a so-called “dosage form”. For example, water-soluble drugs are used in the form of isotonic solutions containing a local anesthetic, while fat-soluble drugs are administered subcutaneously in the form of an oil solution, from which the drug slowly passes into the interstitial fluid.
Earlier, piperidines have been often used as water-soluble salt forms, such as hydrochlorides, to prepare useful dosage forms.
However, along with a high anesthetic effect, such dosage forms also have significant toxicity. Therefore, the preparation of new dosage forms with minimal adverse effects is an actual problem.
The preparation of new dosage forms based on inclusion (host–guest) complexes of cyclodextrins seems to be a promising solution to the problem.
Inclusion complexes are effective as delivery tools. With the conventional type of administration, only nearly one-tenth of the drug molecules can reach the site of application (nerves, tumors, etc.). When the drug is delivered in the form of an inclusion complex and released directly near the site of application, the effective local concentration is increased. Therefore, less amount of drug is required, which can also reduce overall toxicity.
In our previous works [7,13,14,15,16,17,18,19,20,21], we reported the preparation of host–guest complexes of the above piperidines with β-CD and studied their structure (Table 10). All the compounds except MEP formed inclusion complexes with a guest–host ratio of 1:2. For MEP, the 1:1 complex was isolated, which is most likely due to the smaller size of the guest molecule.
The structures of inclusion complexes were studied by NMR during their complex formation in the solutions as well as by X-ray diffraction in their crystalline form. Due to the flexibility of the piperidine ring, piperidines can exist in two main conformations. In inclusion complexes, they can either remain in their starting conformation (for example, BBB) or have a different conformation compared to their free form (kazcaine and prosidol). In addition, in a solution (CDCl3 and D2O), BBB-HCl exists as two isomers in a 2:1 ratio with different orientations of benzoyloxy groups: 1e-(3-n-butoxypropyl)-4a-benzoyloxypiperidine hydrochloride and 1e-(3-n-butoxypropyl)-4e-benzoyloxypiperidine hydrochloride. BBB-HCl forms inclusion complexes with β-CD with a stoichiometry of 2 β-CD:1 BBB-HCl. The same conformation also exists in the inclusion complex isolated in the solid form.
The structure of the inclusion complex of β-CD with MEP (KFCD-7) was studied using NMR and X-ray diffraction [21]. Below (Figure 4), the expansion from the ROESY NMR spectrum in addition to the data published earlier are shown. The cross peaks between inner (3 and 5) protons of β-CD and 2 and 6 protons of the piperidine ring clearly show that the structure of the MEP:β-CD complex in the solution corresponds to the one obtained from the X-ray data in the solid state.
An analysis of the predicted biological activity shows that MEP, as well as its β-CD inclusion complex, should be significantly different in biological activity from the other piperidine derivatives and their inclusion complexes. Because of that, we conducted a pharmacological study of KFCD-7 and compared its acute toxicity, infiltration, and conduction anesthesia with the data for previously obtained piperidine derivatives and reference drugs.

2.3. Pharmacological Study

2.3.1. Infiltration Anesthesia

The test was performed using the Bulbring–Wade method. All the compounds were tested as 0.5% aqua solutions. The results are summarized in Table 11.
As we can see from Table 11, all the drugs have an anesthetic effect that exceeds both novocaine and lidocaine. KFCD-7 shows a slightly longer duration of complete anesthesia than lidocaine, higher than trimecaine in terms of the anesthesia index (35.4 ± 1.3) and duration of complete anesthesia, but less in total duration of anesthesia. The other piperidine derivatives revealed the best values for all parameters of the infiltration anesthesia.
The only exception is kazcaine which has a duration of complete anesthesia comparable to lidocaine but a higher total duration of anesthesia. The formation of an inclusion complex significantly (two times) increases the duration of complete anesthesia up to the KFCD-6 value.
For BVBP and BBB-HCl, the formation of an inclusion complex does not improve their local anesthetic activity. In the case of BBB-HCl, the formation of an inclusion complex significantly (more than two times) reduces the duration of complete anesthesia, while for BVBP, this effect is not so dramatic. The duration of complete anesthesia increases in the following order: procaine < lidocaine < kazcaine < trimecaine < KFCD-7 < BBB-HCl:β-CD < KFCD-4 < KFCD-6 < kazcaine:β-CD < BVBP < BBB-HCl. Total duration of effect: procaine < lidocaine < KFCD-7 < trimecaine < KFCD-4 < kazcaine < KFCD-6 < BVBP < BBB-HCl:β-CD < BBB-HCl < kazcaine:β-CD.
Overall (Figure 5), the kazcaine:β-CD inclusion complex is comparable to BVBP, while KFCD-6 has a slightly shorter duration of complete anesthesia. KFCD-6 and KFCD-4 are better than procaine by 5.9 and 4.8 times, lidocaine by 2.3 and 1.9 times, and trimecaine by 2.0 and 1.6 times, respectively. They have a longer total duration of effect than trimecaine by approximately 2 and 1.7 times, lidocaine by 2.3 and 1.3 times, and procaine by 4.0 and 3.3 times, respectively (statistically significant at p < 0.05).

2.3.2. Conduction Anesthesia

A modified “tail flick” method was used in the study of conduction anesthesia [36]. It was developed at the Department of Pharmacology of the St. Petersburg Medical University, named after Academician I.P. Pavlov. The principle of the method is to determine the latent period of tail withdrawal during the thermal exposure of its middle part with a focused beam of light from an optoelectronic analgesimeter TF-003 before and after anesthesia. The intensity of the thermal nociceptive stimulus is adjusted so that initial tail flick responses occur with a latency ranging from 3 to 6 s.
The activity of compounds and reference drugs for the conduction anesthesia wasstudied in 1% solutions. The following parameters were determined: the rate of onset of anesthesia, the duration of the complete anesthesia, and the total duration of effect.
The results are shown in Table 12. A comparison of the duration of the complete anesthesia and the total duration of effect is shown in Figure 6a,b.
As can be seen from Table 12, all the complexes have an apparent local anesthetic effect, and the rate of anesthesia induction is comparable in all cases.
The duration of complete anesthesia (0.5%): procaine < lidocaine < trimecaine < BBB-HCl:β-CD < BBB-HCl < kazcaine < kazcaine:β-CD
The total duration of effect (0.5%): procaine < lidocaine < trimecaine < BBB-HCl:β-CD < BBB-HCl < kazcaine < kazcaine: β-CD.
The duration of complete anesthesia (1%): procaine < trimecaine < BBB-HCl < lidocaine < KFCD-4 < KFCD-6 < kazcaine < kazcaine:β-CD < BVBP
The total duration of effect (1%): procaine < trimecaine < lidocaine < KFCD-7 < KFCD-4 << kazcaine < KFCD-6 < kazcaine: β-CD ≈ BBB-HCl.
KFCD-7 outperformed all three reference anesthetics for the duration of anesthesia and total anesthetic effect and acted like KFCD-4 (Table 12).
At the above-mentioned concentrations, KFCD-4 and KFCD-7 exceeded procaine for the duration of complete anesthesia by 2 and 1.9 times, trimecaine by 1.3 and 1.4 times, respectively, and acted slightly longer than lidocaine. These solutions also exceeded novocaine and trimecaine in the total duration of a local anesthetic effect (approximately 1.9 and 1.4 times, respectively) and slightly exceeded the effect of lidocaine.
As for the other drugs under consideration, the best result of conduction anesthesia at a 1% solution was exhibited by BVBP, almost three times longer than its complex with CD (KFCD-4); that is, the same picture was observed as for infiltration anesthesia.
The duration of complete anesthesia for KFCD-6 was 89.4 ± 13.4 min, 46.9 ± 8.1 min for trimecaine, 52.7 ± 6.2 for lidocaine, and 34.2 ± 6.9 min for procaine. Thus, the KFCD-6 complex exceeded procaine by 2.3 times, lidocaine by 1.2 times, and trimecaine by 1.7 times (statistically significant at p < 0.001). When comparing the total duration of effect, the KFCD-6 reliably (p < 0.001) exceeded trimecaine by 2.3 times, lidocaine by 2.2 times, and procaine by 3.4 times, respectively.
Kazcaine initially had a good activity (three times better than procaine), and its complex with CD improved the duration of complete anesthesia and the total duration of a local anesthetic effect (but not so dramatically, approximately 30%).
The results for BBB-HCl look interesting. Similar to the infiltration anesthesia, the formation of the complex did not provide an increase in the activity for a 0.5% concentration. However, what is unexpected is that for the 1% concentration, the duration of complete anesthesia was shorter, but the total duration of anesthesia was longer than for the 0.5% concentration. This may probably be due to the different measurement methods used for the 1% solution.

2.3.3. Acute Toxicity

Behavior changes, reflector breath excitability, rate of development and mitigation of external poisoning symptoms, and mortality (LD50) were registered (Figure 7).
The toxic reactions were of the same character for KFCD-4, KFCD-6, and KFCD-7. The higher the dose, the faster poisoning was evident. The phenomena of intoxication began to develop after 20–30 min. The initial stage started with general oppression and resulted in a deferred response, absence of reflex to exogenous irritants, and dyspnea, which later developed into a short period of motional excitation, followed by muscular twitching and clonic–tonic spasms. Mice assumed a lateral position and their breathing became slower and irregular. Death was caused by primary respiratory standstill 30–90 min after injection. The surviving mice recovered from stagnation in 2–2.5 h and were as active as the untreated mice by the end of the first day.
An analysis of the data obtained for the entire group of the drugs under consideration (Table 13) showed that the formation of the inclusion complexes significantly decreases the acute toxicity of substances. The resulting inclusion complexes of piperidine derivatives with β-CD were significantly less toxic than the guests themselves.
The KFCD-6 compound turned out to be the most active and less toxic than procaine by 1.7 times, lidocaine by 3.3 times, and trimecaine by 2.2 times in all experiments (Table 13). KFCD-7 was less toxic than the reference anesthetics.
The most toxic was BBB-HCl, but in the form of an inclusion complex, its toxicity dropped by more than three times and became comparable to procaine. The formation of an inclusion complex reduced the toxicity of AEPP by 2.4 times and BVBP by 2.2 times. The toxicity of kazcaine (which is slightly less than procaine) remained virtually unchanged upon the formation of the inclusion complex, becoming comparable to KFCD-7.

2.3.4. Terminal Anesthesia

The comparison of the activity of the tested compounds with the reference anesthetic, dicaine, was carried out using the Rainier indices, duration of the complete anesthesia, and total duration of effect.
All the studied compounds were tested in 1% and 3% solutions. The experimental results showed that the compounds KFCD-4, KFCD-6, and KFCD-7 in all tested concentrations were significantly inferior both in strength (the Ragnier index) and in the duration of the local anesthetic effect to dicaine and in all concentrations they did not show irritating effects.
At the same time, the formation of inclusion complexes does not always lead to higher activity and depends both on the characteristics of the “guest” and on the type of anesthesia. The most effective in this sense was the inclusion complex of cyclodextrin with 1-(2-ethoxyethyl)-4-ethynyl-4-benzoyloxypiperidine, which is two times better for infiltration anesthesia and 30% better for conduction anesthesia than its salt form (1-(hydrochloride 2-ethoxyethyl)-4-ethynyl-4-benzoyloxypiperidine).
According to the literature, the extension of the alkyl chain at the N atom of the piperidine derivative to the ethoxyethyl substituent leads to the anesthesia index exceeding trimecaine by 1.5 times, lidocaine by 5.1, procaine by 5.3 times, including piperidine derivatives with butoxypropyl substituent. The EC50 value for conduction anesthesia of 1-(3-n-butoxypropyl)-4-benzoyloxypiperidine hydrochloride exceeds the ethoxyethyl homologue by 140 times, and the reference drugs pyromecaine, trimecaine, and procaine by 270, 446, and 670 times, respectively [38].
This pattern is also confirmed by good results for BVBP and BBB-HCl. Elongation of the radical at the nitrogen atom of the piperidine ring from ethoxyethyl to butoxypropyl led to a significant increase in activity during infiltration, especially during the conduction of anesthesia. However, these same drugs have the highest toxicity among those considered. The formation of inclusion complexes leads to a significant reduction in toxicity (comparable to trimecaine) but, at the same time, to a significant reduction in the anesthesia time.

3. Materials and Methods

The following programs were used to study biological activity in silico. The physicochemical and pharmacokinetic properties, including the physicochemical parameters, lipophilicity, absorption, distribution, metabolism, and drug affinity, i.e., the ADME profiles [25], were analyzed on the SwissADME web server (http://www.swissadme.ch/index.php accessed on 7 July 2023). The drug similarity of compounds based on Lipinski’s rule of five was also predicted using the SwissADME web server, and toxicity analysis was carried out with the GUSAR program (https://www.way2drug.com/Gusar/ accessed on 7 July 2023) [32]. To predict possible biological effects, PASS Online open-source software was used [29] (https://www.way2drug.com/PassOnline/ accessed on 12 August 2023). The prognosis of adverse effects was made using ADVER Pred [34] (http://www.way2drug.com/adverpred/ accessed on 12 August 2023). Possible protein targets were evaluated using the Swiss Target Prediction service [39] (http://swisstargetprediction.ch/ accessed on 10 June 2023) and the PASS Targets program [40] (https://www.way2drug.com/passtargets/ accessed on 10 June 2023).
The infiltration anesthesia test was performed with the Bulbring–Wade method [41]. The studies were conducted on male guinea pigs with average masses of 200–250 g. The samples of isotonic solutions of the studied compounds and reference drugs were injected intradermally (0.2 mL) in the back of each animal at four points (vertices of the square with a side of 3 cm) after hair removal. The local anesthetic activity was evaluated six to eight times for each of the selected concentrations. Sensitivity at the injection site was determined by the touch of a blunt injection needle for a series of six touches every 5 min until full recovery.
The depth of anesthesia, expressed as the “anesthesia index” (average of 6 experiments, maximum index-36), the duration of complete anesthesia, and the total duration of the anesthetic effect were determined. The activity of the compounds was compared with the reference drugs, trimecaine, lidocaine, and novocaine, in corresponding concentrations.
The study of conduction anesthesia was carried out using a modified “tail flick” method in rats [36]. It allows one to determine the speed of onset of anesthesia, its depth, the duration of the complete anesthesia, and the total duration of the anesthetic effect of the drug. The study was carried out on outbred white male rats weighing 200–250 g. To study the conduction anesthesia, a solution of a compound or drug (0.5 mL) was injected under the skin of the tail into the area where the thermal effect was applied. The animals in the control group were injected with a saline solution in the same way and same volume. Irritation was applied 1 cm distal from the injection. The first test was carried out 5 min after injection; subsequent tests were carried out every 10 min until the threshold values were completely restored. Doubling of the latent period was taken as complete anesthesia.
Acute toxicity was determined after a single subcutaneous injection of the studied compound and reference drugs in mice (6–8 outbreed albino mice weighing 17.0–22.0 g).
The symptoms of poisoning, speed of onset, severity of regression, and mortality rate were recorded. The animals that survived the first 24 h were monitored in terms of their behavior and full recovery of appetite. The lethal dose (LD50) was calculated using the Miller and Tainter method [42].
All the data obtained were statistically treated.

4. Conclusions

The analysis of the data obtained for the entire group of drugs under consideration shows that the formation of inclusion complexes significantly decreases the acute toxicity of substances.
Based on the results obtained, we can conclude that the inclusion complexes of piperidine derivatives under study are low-toxic local anesthetics, for which further research and development as pharmaceuticals are advisable. Of these, the inclusion complexes of kazcaine and AEPP can be considered the most promising. Moreover, recently obtained fluorine derivatives of kazcaine have shown unexpected antimicrobial activity [43,44].
The pharmacological study results determined that, in terms of local anesthetic activity and acute toxicity, KFCD-7 exceeded all the drugs in comparison but is inferior to all other considered inclusion complexes of piperidine derivatives. The predicted biological activity confirmed the results of the pharmacological study and has shown that both MEP and its complex KFCD-7 are promising molecules for further studies of anticonvulsant effects and effects on reproductive functions.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules29051098/s1, Table S1: The predicted biological activity for the studied compounds.

Author Contributions

Conceptualization, U.K. and V.V.; methodology, U.K., V.V. and V.Y.; formal analysis, investigation, S.Z., V.Y., V.V., M.P., U.K. and K.O.; resources, S.Z., V.Y., V.V., M.P., U.K. and K.O.; writing—original draft preparation, U.K., V.V., M.P. and V.Y.; writing—review and editing, U.K., V.V. and V.Y.; visualization, project administration, V.V. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Ministry of Science and Higher Education of the Republic of Kazakhstan (grant AP19675500).

Institutional Review Board Statement

The animal study protocol was approved by the Local ethical commission (LEC) “Asfendiyarov Kazakh national medical university” non-commercial joint stock company, Extract from the protocol meeting #14(120), meeting date: 28 October 2021.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

We are grateful to the pharmacologists from the Department of Pharmacology of S.D. Asfendiyarov Kazakh National Medical University for carrying out the pharmacological screening of MEP:β-CD. The authors would like to thank the Ministry of Science and Higher Education of the Republic of Kazakhstan (Grant AP19675500).

Conflicts of Interest

The authors declare no conflicts of interest.

References

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Figure 2. The bioavailability radar of the studied compounds based on the physicochemical indices ideal for oral bioavailability.
Figure 2. The bioavailability radar of the studied compounds based on the physicochemical indices ideal for oral bioavailability.
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Figure 3. The probability of adverse effects for the compounds under study.
Figure 3. The probability of adverse effects for the compounds under study.
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Figure 4. ROESY spectrum of the MEP–β-CD complex.
Figure 4. ROESY spectrum of the MEP–β-CD complex.
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Figure 5. The comparison of local anesthetic activity of the compounds and reference drugs for the infiltration anesthesia, using the Bulbring–Wade method (concentration 0.5%).
Figure 5. The comparison of local anesthetic activity of the compounds and reference drugs for the infiltration anesthesia, using the Bulbring–Wade method (concentration 0.5%).
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Figure 6. (a) The comparison of the duration of the complete anesthesia and the total duration of effect for the conduction anesthesia (0.5%). (b) The comparison of the duration of the complete anesthesia and the total duration of effect for the conduction anesthesia (1.0%).
Figure 6. (a) The comparison of the duration of the complete anesthesia and the total duration of effect for the conduction anesthesia (0.5%). (b) The comparison of the duration of the complete anesthesia and the total duration of effect for the conduction anesthesia (1.0%).
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Figure 7. The acute toxicity of the compounds under study and the reference drugs.
Figure 7. The acute toxicity of the compounds under study and the reference drugs.
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Table 1. The compounds used in the present work.
Table 1. The compounds used in the present work.
FormulaCode NameR1R2R3Ref.
1C18H23NO3kazcaine1-(2-ethoxyethyl)-4-ethynyl-4-benzoyl oxypiperidine-C≡CH-(OCO)-C6H5-(CH2)2-O-C2H5[7]
2C18H27NO3prosidol1-(2-ethoxyethyl)-4-phenyl-4-propionyl oxypiperidine-C6H5-(OCO)-C2H5-(CH2)2-O-C2H5[8]
3C19H29NO3·HClBBB·HCl1-(3-n-butoxypropyl)-4-benzoyl oxypiperidine hydrochloride-H-(OCO)-C6H5-(CH2)3-O-C4H9[9]
4C23H31NO3BVBP1-(3-n-butoxypropyl)-4-vinylacetilene-4-benzoyloxypiperidine-C≡C-CH≡CH2-(OCO)-C6H5-(CH2)3-O-C4H9[10]
5C17H25NO3AEPP4-acetoxy-1-(2-ethoxyethyl)-4-phenyl piperidine-C6H5-(OCO)-CH3-(CH2)2-O-C2H5[11]
6C8H13NOMEP1-methyl-4-ethynyl-4-hydroxypiperidine-C≡CH-OH-CH3[12]
7C11H19NO2EEHP1-(2-ethoxyethyl)-4-ethynyl-4-hydroxypiperidine-C≡CH-OH-(CH2)2-O-C2H5[15]
8C15H17NO2MEBP1-methyl-4-ethynyl-4- benzoyl-oxypiperidine-C≡CH-(OCO)-C6H5-CH3[14]
Table 2. Physical and chemical parameters of the studied compounds.
Table 2. Physical and chemical parameters of the studied compounds.
CompoundsPhysical and Chemical Parameters
cLogPlogSMW, g/molTPSA, Å2BioavailabilitySynthetic Accessibility
MEP0.33−0.73139.1923.470.551.88
prosidol3.5−3.1305.4138.770.552.48
kazcaine3.73−3.02301.3838.770.552.76
AEPP3.30−2.79291.3938.770.552.32
BVBP4.93−4.57369.5038.770.553.76
BBB·HCl1.29−4.49355.9039.970.553.33
EEHP1.07−0.96197.2732.700.552.30
MEBP2.42−2.83243.3029.540.552.33
Table 3. The bioavailability criteria for the compounds under study.
Table 3. The bioavailability criteria for the compounds under study.
CompoundsCriteria
LipinskiGhoseVeberEganMuegge *
MEPYesNo: MW < 160YesYesNo: MW < 200
prosidolYesYesYesYesYes
kazcaineYesYesYesYesYes
AEPPYesYesYesYesYes
BVBPYesYesYesYesYes
BBB·HClYesNo: WLOGP < −0.4YesYesYes
EEHPYesYesYesYesNo: MW < 200
MEBPYesYesYesYesYes
* Muegge: MW between 200 and 600 Da, XLogP −2 to 5, TPSA less than 150, number of rings less than 7, number of carbon less than 4, and number of heteroatoms less than 1.
Table 4. The predicted biological activity for 1-methyl-4-ethynyl-4-hydroxypiperidine.
Table 4. The predicted biological activity for 1-methyl-4-ethynyl-4-hydroxypiperidine.
PaPiFBiological Activity
0.8410.0030.838Ovulation inhibitor
0.6900.0100.680Anticonvulsant
0.6780.0040.674Gonadotropin antagonist
0.6730.0060.667Antiosteoporotic
0.6720.0120.660Antisecretoric
0.5810.0160.565Neurotransmitter antagonist
0.5600.0060.554Dementia treatment
0.6110.0860.525Testosterone 17beta-dehydrogenase (NADP+) inhibitor
0.4810.0430.438Antihypoxic
0.4230.0490.374Analeptic
0.3960.0230.373Antialcoholic
0.3710.0070.364Estrogen agonist
0.3930.0300.363Antiparkinsonian
0.4370.0830.354Antiviral (Picornavirus)
0.3840.0340.350Skeletal muscle relaxant
0.3530.0160.337Antiperistaltic
0.3510.0260.325Antitussive
0.3230.0020.321Estradiol 17 beta dehydrogenase stimulant
0.4070.1010.306Alopecia treatment
0.2930.0080.285Contraceptive female
0.3090.0310.278Antiparkinsonian, tremor relieving
0.2870.0270.260Antinaupathic
0.2650.0300.235Antidepressant, Imipramin-like
0.3370.1040.233Analgesic
0.2900.0590.231Cardiovascular analeptic
0.2770.0640.213Antiparasitic
0.2370.0250.212Antihypotensive
0.3980.1860.212Antiischemic. cerebral
0.2730.0680.205Muscle relaxant
0.2090.0030.206Progesterone agonist
0.3200.1160.204Antiseborrheic
0.2730.0710.202Antiparkinsonian, rigidity relieving
0.3170.1290.188Antipruritic, allergic
0.2470.0610.186Sclerosant
0.4010.2150.186Nootropic
0.3150.1410.174Vasoprotector
0.1750.0120.163Female sexual dysfunction treatment
0.1800.0210.159Estrogen antagonist
0.3520.1970.155Antineurotic
0.2620.1200.142Antiviral (Herpes)
0.1530.0140.139Anabolic
0.2030.0680.135Anesthetic
0.2740.1440.130Antipruritic
0.1370.0160.121Androgen antagonist
0.2020.0910.111Diuretic
Table 5. A summary of the predicted biological effects for the studied compounds.
Table 5. A summary of the predicted biological effects for the studied compounds.
Biological ActivityF
MEPProsidolKazcaineAEPPBVBPBBBEEHPMEBPLidocaineProcaine
Anesthetic0.1350.7520.7070.7580.7370.8930.410.4270.7880.923
Anesthetic local-0.7320.6120.7330.7300.8970.3270.3520.7610.914
Analgesic0.2330.589-0.553--- 0.0530.003
Spasmolytic-0.5760.5700.6730.4420.8280.3580.3670.4700.749
Spasmolytic, urinary-0.6040.6700.6140.3970.6720.6160.4470.7220.804
Spasmolytic, Papaverin-like-0.5130.6850.4520.5740.839--0.2240.786
Anticonvulsant0.6800.5420.5260.5110.082-0.6480.5620.6080.726
Antidepressant, Imipramin-like0.235-------0.0840.197
Skeletal muscle relaxant-0.3270.2720.1860.067---0.3340.684
Table 6. The summary of the most probable macromolecular targets for the studied compounds study (SwissTargetPrediction).
Table 6. The summary of the most probable macromolecular targets for the studied compounds study (SwissTargetPrediction).
ProteinConfidenceCHEMBL ID
MEP
Phenylethanolamine N-methyltransferase0.033970689612CHEMBL4617
Aminopeptidase N0.033970689612CHEMBL1907
prosidol
Dopamine D3 receptor0.127302569502CHEMBL234
Vesicular acetylcholine transporter0.127302569502CHEMBL4767
Sigma opioid receptor0.119403562123CHEMBL287
Dopamine D2 receptor0.119403562123CHEMBL217
Mu opioid receptor0.119403562123CHEMBL233
Serotonin 1a (5-HT1a) receptor0.119403562123CHEMBL214
kazcaine
Muscarinic acetylcholine receptor M40.11150186548CHEMBL1821
Muscarinic acetylcholine receptor M20.11150186548CHEMBL211
Muscarinic acetylcholine receptor M10.11150186548CHEMBL216
Muscarinic acetylcholine receptor M30.11150186548CHEMBL245
Dual specificity mitogen-activated protein kinase kinase 10.11150186548CHEMBL3587
AEPP
Vesicular acetylcholine transporter0.122581769115CHEMBL4767
Dopamine D3 receptor0.114337558605CHEMBL234
Serotonin 1a (5-HT1a) receptor0.106099949133CHEMBL214
Dopamine transporter0.106099949133CHEMBL238
Serotonin transporter0.106099949133CHEMBL228
BVBP
Butyrylcholine sterase0.113285953487CHEMBL1914
Cathepsin D0.113285953487CHEMBL2581
Beta-secretase 10.113285953487CHEMBL4822
Beta secretase 20.113285953487CHEMBL2525
Melanin-concentrating hormone receptor 10.113285953487CHEMBL344
Dopamine transporter0.113285953487CHEMBL238
BBB
Butyrylcholine sterase0.259910103952CHEMBL1914
Dopamine transporter (by homology)0.234886157898CHEMBL238
Neuronal acetylcholine receptor protein alpha-7 subunit0.151564691457CHEMBL2492
Dopamine D3 receptor0.118277084772CHEMBL234
Serotonin transporter0.109945769839CHEMBL228
Norepinephrine transporter0.109945769839CHEMBL222
Sigma opioid receptor0.109945769839CHEMBL287
EEHP
Purine nucleoside phosphorylase0.0312265582077CHEMBL4338
Dipeptidyl peptidase IV0.0312265582077CHEMBL284
Glutathione reductase0.0312265582077CHEMBL2755
Histamine H1 receptor0.0312265582077CHEMBL231
Adrenergic receptor beta0.0312265582077CHEMBL210
Mu opioid receptor0.0312265582077CHEMBL233
Delta opioid receptor0.0312265582077CHEMBL236
Kappa Opioid receptor0.0312265582077CHEMBL237
MEBP
Neuronal acetylcholine receptor protein alpha-7 subunit0.0626219668353CHEMBL2492
Dopamine transporter (by homology)0.0535560755162CHEMBL238
Serotonin transporter0.0535560755162CHEMBL228
Norepinephrine transporter0.0535560755162CHEMBL222
Butyrylcholinesterase0.0535560755162CHEMBL1914
Calcium-activated potassium channel subunit alpha-10.0535560755162CHEMBL4304
Muscarinic acetylcholine receptor M40.0535560755162CHEMBL1821
Muscarinic acetylcholine receptor M20.0535560755162CHEMBL211
Muscarinic acetylcholine receptor M10.0535560755162CHEMBL216
Muscarinic acetylcholine receptor M30.0535560755162CHEMBL245
Table 7. The summary of the most probable macromolecular targets for the compounds under study (PASS Targets).
Table 7. The summary of the most probable macromolecular targets for the compounds under study (PASS Targets).
ProteinConfidenceCHEMBL ID
MEP
Mitogen-activated protein kinase 20.9067CHEMBL5914
Receptor-interacting serine/threonine-protein kinase 40.8996CHEMBL6083
Serine/threonine-protein kinase TNNI3K0.8883CHEMBL5260
G protein-coupled receptor kinase 40.8847CHEMBL5861
Serine/threonine-protein kinase MRCK gamma0.8825CHEMBL5615
Cytochrome P450 2J20.8796CHEMBL3491
Mitogen-activated protein kinase kinase kinase 30.8738CHEMBL5970
Receptor tyrosine-protein kinase erbB-30.8062CHEMBL5838
Homeodomain-interacting protein kinase 40.7941CHEMBL1075167
Serine/threonine-protein kinase PAK 20.7799CHEMBL4487
Serine/threonine-protein kinase SBK10.7459CHEMBL1163129
Non-receptor tyrosine-protein kinase TNK10.7259CHEMBL5334
Phosphatidylinositol-5-phosphate 4-kinase type-2 gamma0.7252CHEMBL1770034
Dual specificity mitogen-activated protein kinase kinase 50.7208CHEMBL4948
Myotonin-protein kinase0.7085CHEMBL5320
Serine/threonine-protein kinase SIK20.7003CHEMBL5699
Chaperone activity of bc1 complex-like, mitochondrial0.6945CHEMBL5550
Eukaryotic translation initiation factor 2-alpha kinase 40.6845CHEMBL5358
myosin light chain kinase 20.6843CHEMBL2777
Citron Rho-interacting kinase0.6825CHEMBL5579
Leukocyte tyrosine kinase receptor0.6690CHEMBL5627
Uncharacterized aarF domain-containing protein kinase 40.6620CHEMBL5753
Ephrin type-A receptor 60.6481CHEMBL4526
Adaptor-associated kinase0.6397CHEMBL3830
BMP-2-inducible protein kinase0.6356CHEMBL4522
Cytochrome P450 2B60.6337CHEMBL4729
Serine/threonine-protein kinase SRPK30.6272CHEMBL5415
Serine/threonine-protein kinase 20.6263CHEMBL4202
Phosphatidylinositol-4-phosphate 5-kinase type-1 gamma0.6195CHEMBL1908383
Ephrin type-B receptor 60.5917CHEMBL5836
Tyrosine-protein kinase CSK0.5881CHEMBL2634
Serine/threonine-protein kinase 32A0.5826CHEMBL6150
Serine/threonine-protein kinase 360.5790CHEMBL4312
Tyrosine-protein kinase receptor Tie-10.5712CHEMBL5274
Serine/threonine-protein kinase OSR10.5647CHEMBL1163104
Serine/threonine-protein kinase PAK70.5536CHEMBL4524
Peripheral plasma membrane protein CASK0.5385CHEMBL1908381
Serine/threonine-protein kinase NEK90.5364CHEMBL5257
Ephrin type-A receptor 80.5318CHEMBL4134
Estrogen receptor beta0.5299CHEMBL242
Serine/threonine-protein kinase PAK60.5149CHEMBL4311
Ribosomal protein S6 kinase alpha 40.5134CHEMBL3125
Serine/threonine-protein kinase GAK0.5085CHEMBL4355
prosidol
Cytochrome P450 2J20.6717CHEMBL3491
Alpha-2b adrenergic receptor0.3277CHEMBL1942
Muscarinic acetylcholine receptor M40.2869CHEMBL1821
Muscarinic acetylcholine receptor M10.2819CHEMBL216
HERG0.2806CHEMBL240
Protein kinase C iota0.2505CHEMBL2598
Histamine H1 receptor0.2256CHEMBL231
kazcaine
Cytochrome P450 2J20.7927CHEMBL3491
Receptor-interacting serine/threonine-protein kinase 40.7786CHEMBL6083
Serine/threonine-protein kinase MRCK gamma0.7107CHEMBL5615
G protein-coupled receptor kinase 40.7034CHEMBL5861
Mitogen-activated protein kinase kinase kinase 20.6794CHEMBL5914
Mitogen-activated protein kinase kinase kinase 30.6458CHEMBL5970
Serine/threonine-protein kinase SBK10.6177CHEMBL1163129
Receptor tyrosine-protein kinase erbB-30.4501CHEMBL5838
Serine/threonine-protein kinase SIK20.4465CHEMBL5699
Eukaryotic translation initiation factor 2-alpha kinase 40.4396CHEMBL5358
P-glycoprotein 10.4321CHEMBL4302
Non-receptor tyrosine-protein kinase TNK10.4268CHEMBL5334
myosin light chain kinase 20.4165CHEMBL2777
Cytochrome P450 2B60.4009CHEMBL4729
Chaperone activity of bc1 complex-like, mitochondrial0.3753CHEMBL5550
Serine/threonine-protein kinase TNNI3K0.3750CHEMBL5260
Homeodomain-interacting protein kinase 40.3685CHEMBL1075167
Ephrin type-A receptor 60.3551CHEMBL4526
Citron Rho-interacting kinase0.3370CHEMBL5579
Cytochrome P450 2C90.3326CHEMBL3397
Phosphatidylinositol-5-phosphate 4-kinase type-2 gamma0.3296CHEMBL1770034
Plectin0.2866CHEMBL1293240
Protein kinase C iota0.2864CHEMBL2598
Leukocyte tyrosine kinase receptor0.2831CHEMBL5627
Estrogen receptor beta0.2721CHEMBL242
Muscarinic acetylcholine receptor M40.2553CHEMBL1821
Myotonin-protein kinase0.2550CHEMBL5320
Ephrin type-B receptor 60.2545CHEMBL5836
AEPP
Cytochrome P450 2J20.6780CHEMBL3491
P-glycoprotein 10.4892CHEMBL4302
Alpha-2b adrenergic receptor0.3261CHEMBL1942
Cytochrome P450 2D60.3077CHEMBL289
Protein kinase C iota0.2962CHEMBL2598
Muscarinic acetylcholine receptor M10.2911CHEMBL216
Muscarinic acetylcholine receptor M40.2855CHEMBL1821
Histamine H1 receptor0.2280CHEMBL231
BVBP
Serine/threonine-protein kinase 350.3745CHEMBL5651
Cytochrome P450 2J20.3266CHEMBL3491
Plectin0.2873CHEMBL1293240
Muscarinic acetylcholine receptor M20.2740CHEMBL211
Receptor tyrosine-protein kinase erbB-30.2663CHEMBL5838
Mitogen-activated protein kinase kinase kinase 30.2531CHEMBL5970
Serine/threonine-protein kinase SIK30.2523CHEMBL6149
BBB
P-glycoprotein 10.5329CHEMBL4302
Cytochrome P450 2J20.3725CHEMBL3491
Serine/threonine-protein kinase 350.3521CHEMBL5651
Muscarinic acetylcholine receptor M50.3343CHEMBL2035
Microtubule-associated serine/threonine-protein kinase 10.3154CHEMBL1163128
Mitogen-activated protein kinase 60.3104CHEMBL5121
Serine/threonine-protein kinase PFTAIRE-10.3071CHEMBL6162
Protein kinase C alpha0.2654CHEMBL299
Muscarinic acetylcholine receptor M40.2492CHEMBL1821
Serotonin 3a (5-HT3a) receptor0.2476CHEMBL1899
EEHP
Cytochrome P450 2J20.8460CHEMBL3491
Receptor-interacting serine/threonine-protein kinase 40.8042CHEMBL6083
Serine/threonine-protein kinase MRCK gamma0.8001CHEMBL5615
Mitogen-activated protein kinase kinase kinase 20.7452CHEMBL5914
G protein-coupled receptor kinase 40.7240CHEMBL5861
Mitogen-activated protein kinase kinase kinase 30.7050CHEMBL5970
Serine/threonine-protein kinase PAK 20.6813CHEMBL4487
Serine/threonine-protein kinase SBK10.6791CHEMBL1163129
Receptor tyrosine-protein kinase erbB-30.6538CHEMBL5838
Serine/threonine-protein kinase TNNI3K0.6324CHEMBL5260
Chaperone activity of bc1 complex-like, mitochondrial0.5796CHEMBL5550
Cytochrome P450 2B60.5447CHEMBL4729
Eukaryotic translation initiation factor 2-alpha kinase 40.5391CHEMBL5358
Serine/threonine-protein kinase SIK20.5357CHEMBL5699
Estrogen receptor beta0.5281CHEMBL242
Citron Rho-interacting kinase0.5175CHEMBL5579
MEBP
Receptor-interacting serine/threonine-protein kinase 40.8715CHEMBL6083
Mitogen-activated protein kinase kinase kinase 20.8575CHEMBL5914
G protein-coupled receptor kinase 40.8548CHEMBL5861
Serine/threonine-protein kinase MRCK gamma0.8136CHEMBL5615
Cytochrome P450 2J20.8101CHEMBL3491
Mitogen-activated protein kinase kinase kinase 30.7846CHEMBL5970
Serine/threonine-protein kinase TNNI3K0.7075CHEMBL5260
Homeodomain-interacting protein kinase 40.7053CHEMBL1075167
Non-receptor tyrosine-protein kinase TNK10.6899CHEMBL5334
Serine/threonine-protein kinase SBK10.6805CHEMBL1163129
Phosphatidylinositol-5-phosphate 4-kinase type-2 gamma0.6226CHEMBL1770034
myosin light chain kinase 20.6214CHEMBL2777
Serine/threonine-protein kinase SIK20.6165CHEMBL5699
Eukaryotic translation initiation factor 2-alpha kinase 40.5802CHEMBL5358
Leukocyte tyrosine kinase receptor0.5779CHEMBL5627
Receptor tyrosine-protein kinase erbB-30.5648CHEMBL5838
Tyrosine-protein kinase receptor Tie-10.5502CHEMBL5274
Ephrin type-A receptor 60.5471CHEMBL4526
BMP-2-inducible protein kinase0.5423CHEMBL4522
Adaptor-associated kinase0.5418CHEMBL3830
Chaperone activity of bc1 complex-like, mitochondrial0.5405CHEMBL5550
Cytochrome P450 2B60.5163CHEMBL4729
Myotonin-protein kinase0.5140CHEMBL5320
Table 8. The results of the predicted acute toxicity for the studied compounds.
Table 8. The results of the predicted acute toxicity for the studied compounds.
Rat LD50 for Different Routes of Administration *Meaning/Acceptability **
MEPProsidolKazcaineAEPPBVBPEEHPMEBP
IP (mg/kg)92.5206.5343.5229.3362.8122.3245.2
IP (log10, mmol/kg)−0.190−0.170-−0.104−0.008−0.2080.003
IP acute toxic class4444444
IV (mg/kg)27.9133.25343.5031.7326.5528.5223.67
IV (log10, mmol/kg)−0.710−0.963-−0.963−1.1440.389−1.012
IV acute toxic class3353333
Oral (mg/kg)332.3557.5343.5570.4881.7483.7439.0
Oral (log10, mmol/kg)0.3650.261-0.2920.3780.3890.256
Oral acute toxic class4444444
SC (mg/kg)105.0275.0343.5235.1265.1273.0394.8
SC LD50 0.1410.210
SC acute toxic class3444444
* IP—intraperitoneal route of administration, IV—intravenous route of administration, Oral—oral route of administration, and SC—subcutaneous route of administration. ** BOLD = in AD: the compound falls within the range of applicability of the models; italic = out of AD: compound outside the range of applicability of models.
Table 9. The prognosis of adverse effects for the compounds under study.
Table 9. The prognosis of adverse effects for the compounds under study.
Compound Pa *Pi *PAdverse Effect
MEP0.7840.0660.718hepatotoxicity
prosidol0.4160.1720.244arrhythmia
kazcaine0.3060.2950.011arrhythmia
0.7290.0890.640hepatotoxicity
0.2760.2580.018myocardial infarction
0.2640.1970.067nephrotoxicity
AEPP0.4390.1560.283arrhythmia
0.3330.3180.015hepatotoxicity
BVBP0.5710.0600.511arrhythmia
BBB **0.6780.0290.649arrhythmia
EEHP0.7290.0890.640hepatotoxicity
0.2630.1980.065nephrotoxicity
MEBP0.7880.0640.724hepatotoxicity
0.3090.1800.129myocardial infarction
* Pa—probability of activity; Pi—probability of inactivity. ** only as a base.
Table 10. The studied compounds and their host–guest complexes with β-CD.
Table 10. The studied compounds and their host–guest complexes with β-CD.
#Molecule NameRGuest/β-CDMass Guest/Host/ComplexIncluded Part of the Guest
1MEPH1/1139/1135/1274Full inclusion
2kazcaineCOC6H51/2301/2270/25711-2-ethoxyethyl and piperidine
3AEPPCH31/2291/2270/25611-(2-ethoxyethyl)-4-phenylpiperidine
prosidolCH2CH31/2305/2270/2575Full inclusion
4BBB·HClH1/2319/2270/25891-(3-n-butoxypropyl) and 4-benzoyloxy
BVBPCCCHCH21/2370/2270/26401-(3-n-butoxypropyl) and 4-benzoyloxy-piperidine
Table 11. The local anesthetic activity of the compounds and reference drugs for the infiltration anesthesia, using the Bulbring-Wade method.
Table 11. The local anesthetic activity of the compounds and reference drugs for the infiltration anesthesia, using the Bulbring-Wade method.
Compound (Code), Concentration, %Anesthesia Index (M ± m)The Duration of Complete Anesthesia (min.), (M ± m)Total Duration of the Effect (min.), (M ± m)Ref.
kazcaine, 1%-67.4 ± 1.9101.9 ± 3.5[7]
kazcaine: β-CD (1:2), 1%-121.3 ± 4.3 a136.1 ± 1.7 a[7]
kazcaine, 0.5%-26.3 ± 2.982.9 ± 3.6[7]
kazcaine: β-CD (1:2) b, 0,5%-63.3 ± 2.9108.4 ± 2.7[7]
BVBP, 0.5%36.0 ± 065.0 ± 090.0 ± 1.3[18]
BVBP:β-CD (1:2), 0.5% (KFCD-4)36.0 ± 048.0 ± 4.573.3 ± 2.1[18]
BBB-HCl, 0.25%-23.3 ± 3.835.0 ± 2.7[35]
BBB-HCl, 0.5%-94.2 ± 1.5102.5 ± 2.1[35]
BBB-HCl: β-CD (1:2), 0.5%35.0 ± 1.440.0 ± 2.6 d93.3 ± 3.1 c[18]
AEPP:β-CD (1:2), 0.5% (KFCD-6)36.0 ± 1.359.0 ± 2.787.1 ± 4.2[20]
MEP: β-CD, 0.5% (KFCD-7)35.4 ± 1.333.3 ± 1.647.8 ± 3.6This work
procaine, 1%-20.1 ± 1.642.0 ± 1.2[7]
trimecaine, 0.5%34.1 ± 0.530.0 ± 1.754.5 ± 2.3[20]
lidocaine, 0.5%32.3 ± 2.325.8 ± 0.844.1 ± 1.7[20]
procaine, 0.5%30.0 ± 0.210.0 ± 022.0 ± 0.1[20]
a Deviations in relation to reference preparations are statistically authentic at p < 0.001. b By mass kazcaine is 1/10 of the complex. c Deviations in relation to the reference preparations are statistically authentic at: lidocaine—pi < 0.05, trimecaine—pi < 0.001, procaine—pi < 0.02. d statistically authentic at: lidocaine—pi < 0.05, trimecaine—pi < 0.01, procaine—pi < 0.001.
Table 12. The local anesthetic activity of compounds and reference drugs for the conduction anesthesia.
Table 12. The local anesthetic activity of compounds and reference drugs for the conduction anesthesia.
Compound (Code)The Duration of the Complete Anesthesia (min.), (M ± m)The Total Duration of Effect (min.), (M ± m)Ref.
concentration0.5%1%0.5%1%
kazcaine74.4 ± 11.1103.4 ± 11.197.6 ± 6.3119.6 ± 5.5[7]
kazcaine: β-CD (1:2)106.1 ± 2.0 a137.1 ± 3.9 b118.9 ± 6.8 a147.5 ± 6.7 a[7]
BVBP60180--
BVBP:β-CD (1:2) KFCD-4-68.2 ± 6.7 d-80.5 ± 12.0 d
BBB-HCl67.5 ± 3.4 f50.8 ± 3.0 e86.7 ± 3.6 f150.8 ± 4.7 e[35]
BBB-HCl: β-CD (1:2)62.5 ± 1.2 c,d-83.3 ± 2.4 c,d-[18]
AEPP:β-CD (1:2) KFCD-6-89.4 ± 13.4 d-138.5 ± 14.8 d[20]
MEP----
MEP:β-CD (1:1) KFCD-7-66.2 ± 10.5 d-73.5 ± 11.3 dThis work
trimecaine33.7 ± 11.2 d46.9 ± 8.1 d45.8 ± 13.2 d58.1 ± 11.4 d[18,20]
lidocaine28.0 ± 5.4 d52.7 ± 6.4 d45.0 ± 4.7 d63.1 ± 16.2 d[18,20]
procaine15.2 ± 3.9 d34.2 ± 6.9 d30.4 ± 4.2 d41.3 ± 14.6 d[18,20]
a Deviations in relation to reference preparations are statistically authentic at p < 0.001. b Deviations in relation to kazcaine are statistically authentic at p < 0.01. c Deviations in relation to reference preparations are statistically authentic at: lidocaine—pi < 0.05, trimecaine—pi < 0.001, procaine—pi < 0.02. d rate of anesthesia induction—3 min. e Local anesthetic activity for the conduction anesthesia, using the method of electrical stimulation of a rabbit inferior dental nerve. f Local anesthetic activity for the conduction anesthesia, using a modified “tail flick” method.
Table 13. The acute toxicity of the compounds under study and the reference drugs.
Table 13. The acute toxicity of the compounds under study and the reference drugs.
CompoundLD50 (mg/kg)pRef.
kazcaine529.3 ± 7.1 [7]
kazcaine: β-CD (1:2) *590.0 ± 11.3 [7]
BVBP316 [37]
BVBP: β-CD (1:2) (KFCD-4)700.0 ± 25.4 [18]
BBB-HCl138 [35]
BBB-HCl: β-CD (1:2)478.5 ± 8.0 [18]
AEPP340 [37]
AEPP:β-CD (1:2) (KFCD-6) **830.0 ± 34.5 [20]
MEP:β-CD (KFCD-7) **622.4 ± 22.9 This work
procaine480.0 ± 9.8 p1[18]
lidocaine248.6 ± 18.4p2[18]
trimecaine378.2 ± 19.4p3[7]
* Deviations for this complex compared to the reference preparations are statistically authentic at pi < 0.001. ** Deviations for the KFCD-6 and KFCD-7 compared to the reference preparations are statistically authentic at p1 < 0.01; p2 and p3 < 0.005.
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Kemelbekov, U.; Volynkin, V.; Zhumakova, S.; Orynbassarova, K.; Papezhuk, M.; Yu, V. Comparative Analysis of the Structure and Pharmacological Properties of Some Piperidines and Host–Guest Complexes of β-Cyclodextrin. Molecules 2024, 29, 1098. https://doi.org/10.3390/molecules29051098

AMA Style

Kemelbekov U, Volynkin V, Zhumakova S, Orynbassarova K, Papezhuk M, Yu V. Comparative Analysis of the Structure and Pharmacological Properties of Some Piperidines and Host–Guest Complexes of β-Cyclodextrin. Molecules. 2024; 29(5):1098. https://doi.org/10.3390/molecules29051098

Chicago/Turabian Style

Kemelbekov, Ulan, Vitaly Volynkin, Symbat Zhumakova, Kulpan Orynbassarova, Marina Papezhuk, and Valentina Yu. 2024. "Comparative Analysis of the Structure and Pharmacological Properties of Some Piperidines and Host–Guest Complexes of β-Cyclodextrin" Molecules 29, no. 5: 1098. https://doi.org/10.3390/molecules29051098

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