Балансування фізико-хімічних властивостей між молекулами милосердя (неадиктивними препаратами) і молекулами містицизму (часто адиктивними препаратами)

Kraus, Jean-Louis

doi:10.24959/ophcj.25.321860

Балансування фізико-хімічних властивостей між молекулами милосердя (неадиктивними препаратами) і молекулами містицизму (часто адиктивними препаратами)

The fundamental physicochemical features of drugs acting on the central nervous system (CNS) determine their ability to penetrate the blood-brain barrier (BBB) and be active against the CNS activities. In this paper, we study two well-known groups of drugs used or prescribed by physicists to treat C...

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Veröffentlicht in:	Журнал органічної та фармацевтичної хімії
Datum:	2025
Jahrgang:	23
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Сторінки:	3-10
ISSN:	2518-1548
Автори та афіліації:	Jean-Louis Kraus — Institut de Biologie du Développement de Marseille
1. Verfasser:	Kraus, Jean-Louis
Format:	Artikel
Sprache:	Englisch
Veröffentlicht:	National University of Pharmacy 2025
Schlagworte:	розробка препаратів для ЦНС анальгетики психоактивні препарати фізико-хімічні властивості терапевтичні препарати
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Journal of Organic and Pharmaceutical Chemistry

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description	The fundamental physicochemical features of drugs acting on the central nervous system (CNS) determine their ability to penetrate the blood-brain barrier (BBB) and be active against the CNS activities. In this paper, we study two well-known groups of drugs used or prescribed by physicists to treat CNS disorders. One group of drugs belongs to pain killers (the Molecules of Mercy), and the other group belongs to the mind-changers (the Molecules of Mysticism). These two groups of CNS drugs differ in a number of physicochemical parameters: molecular weight, lipophilicity, hydrogen bound acceptor count, hydrogen bond donor count, polar surface area, polarizability, flexibility, bioavailability, and their behavior (agreement or disagreement) related to specific structural conditions, in particular the Lipinski’s rule, Ghose filter, Veber’s rule, Multi-Drug Data Report (MDDR) criteria. In the study of 41 well-known drugs that affect the CNS (both approved or illegal), it has been found that painkillers that do not cause addiction have a physicochemical profile other than those of mind-changer drugs that are very often addictive. The features of physicochemical parameters associated with the profiles of “pain killer” and “mind-changer” drugs are discussed.
doi_str_mv	10.24959/ophcj.25.321860
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fulltext	ISSN 2308-8303 (Print) / 2518-1548 (Online) 3 Opinion http://ophcj.nuph.edu.ua UDC 615.214:544 J.-L. Kraus Institut de Biologie du Développement de Marseille, UMR 7288. CNRS. Aix Marseille University, Case 907, Parc Scientifique de Luminy, 13288 Marseille Cedex 9, France Balancing Physicochemical Properties between the Molecules of Mercy (Non-Addictive Drugs) and the Molecules of Mysticism (Often Addictive Drugs) Abstract The fundamental physicochemical features of drugs acting on the central nervous system (CNS) determine their ability to penetrate the blood-brain barrier (BBB) and be active against the CNS activities. In this paper, we study two well-known groups of drugs used or prescribed by physicists to treat CNS disorders. One group of drugs belongs to pain killers (the Molecules of Mercy), and the other group belongs to the mind-changers (the Molecules of Mysticism). These two groups of CNS drugs differ in a number of physicochemical parameters: molecular weight, lipophilicity, hydrogen bound acceptor count, hydrogen bond donor count, polar surface area, polarizability, flexibility, bioavailability, and their behavior (agreement or disagree- ment) related to specific structural conditions, in particular the Lipinski’s rule, Ghose filter, Veber’s rule, Multi-Drug Data Report (MDDR) criteria. In the study of 41 well-known drugs that affect the of the CNS (both approved or illegal), it has been found that painkillers that do not cause addiction have a physicochemical profile other than those of mind-changer drugs that are very often addictive. The features of physicochemical parameters associated with the profiles of “pain killer” and “mind-changer” drugs are dis- cussed. Keywords: CNS-drugs discovery; pain killers; mind-changers; physicochemical properties; therapeutic drugs Ж.-Л. Краус Марсельський інститут біології розвитку, UMR 7288. CNRS. Екс-Марсельський університет, корпус 907, Науковий парк Люміні, 13288 Марсель Седекс 9, Франція Балансування фізико-хімічних властивостей між молекулами милосердя (неадиктивними препаратами) і молекулами містицизму (часто адиктивними препаратами) Анотація Фундаментальні фізико-хімічні характеристики лікарських засобів, що діють на центральну нервову систему (ЦНС), ви- значають їхню здатність проникати через гематоенцефалічний бар’єр (ГЕБ) і проявляти активність щодо ЦНС. У цій ро- боті досліджено дві відомі групи препаратів, які застосовують для лікування розладів ЦНС. Перша група належить до анальгетиків (молекули милосердя), а друга – до психоактивних речовин (молекули містицизму). Ці дві групи лікар- ських засобів відрізняються за деякими фізико-хімічними параметрами: молекулярною масою, ліпофільністю, кіль- кістю акцепторів і донорів водневого зв’язку, площею полярної поверхні, поляризованістю, «гнучкістю», біодоступніс- тю, а також за відповідністю або невідповідністю певним структурним критеріям, зокрема правилу Ліпінскі, фільтру Гоуза, правилу Вебера та критеріям Multi-Drug Data Report (MDDR). У ході дослідження 41 добре відомого лікарського засобу, що впливають на ЦНС (як затверджених, так і нелегальних), було виявлено, що анальгетики, які не викликають залежності, мають фізико-хімічний профіль, відмінний від профілю психоактивних речовин, які часто є адиктивними. У статті розглянуто особливості фізико-хімічних параметрів, пов’язані з профілями «анальгетичних препаратів» та «психоактивних препаратів». Ключові слова: розробка препаратів для ЦНС; анальгетики; психоактивні препарати; фізико-хімічні властивості; терапевтичні препарати ISSN 2308-8303 (Print) / 2518-1548 (Online) 4 Журнал органічної та фармацевтичної хімії 2025, 23 (1) Citation: Kraus, J.-L. Balancing Physicochemical Properties between Molecules of the Mercy (Non-Addictive Drugs) and Molecules of Mysticism (Often Addictive Drugs) Journal of Organic and Pharmaceutical Chemistry 2025, 23 (1), 3 – 10. https://doi.org/10.24959/ophcj.25.321860 Received: 17 October 2024; Revised: 30 January 2025; Accepted: 5 February 2025 Copyright© 2025, J.-L. Kraus. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0). Funding: CNRS-Aix Marseille-University and Marseille Institute for Biology of Development (IBDM) are greatly acknowledged for the facilities offered and financial support. Conflict of interest: The author has no conflict of interest to declare. Ethics approval and consent to participate: This article does not contain any studies involving patients or animals as test objects. ■ Introduction At all times, throughout his evolution and de- velopment, man has sought to protect himself against pain, whether physical or psychological. At first, he was looking for plants or natural com- pounds for this purpose. Then, taking care of the health and well-being, a person was seeking for new flavors, new tastes, new antibacterial drugs and new hormone regulators. Throughout this time, man has been creating a pharmacopoeia that contains several thousand molecules with a wide variety of chemical structures. Some of these molecules are of natural origin, while most of them are obtained as a result of chemical syn- thesis. Today, in order to cure specific patholo- gies or disorders, medical professionals have to make difficult choices between thousands of pos- sible therapeutic molecules. In their book, “Organic Molecules in Action” (1973), Murray Goodman and Frank Morehouse [1] have proposed to classify the pharmacopeial constitutive molecules into several classes of com- pounds, which represent millions of combinations between carbon, hydrogen, oxygen, sulfur, and other atoms upon which life itself is based: • the Molecules of the code of life (nucleic acid and proteins); • the Giant molecules (polymers); • the Molecules of Mercy (pain killers or pain relievers); • the Molecules of Mysticism (mind-changers); • the Molecules of Might (germ killers); • the Molecules of the steroid family (hormo- nal modulators); • the Molecules of Growth and Health (vitamins); • the Molecules of Senses (taste, odor, attrac- tion). Among these different classes of molecules, the Molecules of Mercy (pain relievers or pain kil- lers) and the Molecules of Mysticism appeared of particular interest since both classes act at the Central Nervous System level (CNS), which requires crossing the blood-brain barrier (BBB). This article will focus on these two groups of drugs, emphasizing their physicochemical prop- erties that enable them to act as pain killers or as mind changers. From medicinal and chemical perspectives, the ability to design efficient pain reliever drugs in reducing their psychedelic side effect (mind changers) could be of high interest. ■ Materials and methods The drugs included in this study are appro- ved by the Food and Drug Administration (FDA) or have received approval from the European Me- dicines Agency (EMA). Some of these drugs are approved, others are banned, and some are ob- solete molecules that have been replaced. How- ever, all the drugs mentioned in this manuscript have been tested on patients for their effects on the CNS and are registered in the DrugBank da- tabase available at www.drugbank.com. Accord- ing to literature recommendations, CNS drugs mentioned in this study are classified into two groups of drugs – pain killers (drugs of Mercy) and mind-changers (drugs of Mysticism) [1]. The group of Pain killers (Molecules of Mercy) Pain killers or pain reliever molecules (Mole- cules of Mercy) are used to alleviate the common human aches and pains. Their action is often me- diated through the prostaglandin production. The prostaglandin change is generally very low in uninflamed tissues, but increases immediately in acute inflammation [2]. Nevertheless, some com- pounds like capsaicin, codeine, and buprenorphi- ne, listed below, do not act through the inhibi- tion of prostaglandin effects. The branded names of the drugs included in this group of painkillers, which refer to the inter- national non-proprietary names (INN), are the fol- lowing: Salicylic acid, Codeine, Buprenorphine, Methadone, Nalorphine, Celecoxib, Ibuprofen, Na- proxen, Paracetamol, Pregabalin, Diclofenac, Oxy- codone, Carbamazepine, Amitriptyline, Capsaicin, Meloxicam, Prednisolone, Meperidine, Butalbital, Naltrexone, Gabapentin, Morphine and Fentanyl§. § Note: it should be underlined that in this study Fentanyl and Morphine have been considered as Pain Killers, as well as Mind Changers. ISSN 2308-8303 (Print) / 2518-1548 (Online) 5 Journal of Organic and Pharmaceutical Chemistry 2025, 23 (1) The group of Mind-Changer Drugs (Mole- cules of Mysticism) These molecules affect mental processes and fall under the classification of hallucinogenic or psychotomimetic drugs. They alter thinking, per- ception, and mood [3]. The international nonpro- prietary names of drugs belonging to the group of mind changers are as follows: Heroin, Cocaine, Er- gotamine, LSD, Mescaline, Amphetamine, Psy- locibin, Nikethamide, Serotonin, Epinephrine, Phe- nylethylamine, Methamphetamine, Bufotenine, Tetrahydrocannabinol, Methylphenidate (Ritalin), Cathinone, Morphine, and Fentanyl§. This study does not include prescribed drugs available to treat mental illness. Antidepressants used to treat depression, anxiety, and some types of personality disorders, or antipsychotic drugs to treat schizophrenia and bipolar disorders, as well as to restore the chemical balance of the brain are not mentioned [4]. The study present- ed includes only modern medicines, natural or synthetic, which are known to be active against the CNS as pain relievers or mind changers. ■ Results Physical and chemical properties of the drugs studied (pain killers and mind-chan- gers) In the broad sense, moderately lipophilic drugs cross the BBB, by passive diffusion, and the hy- drogen bonding properties of drugs can signifi- cantly influence their CNS uptake profile. Polar molecules are generally poor CNS drugs unless they undergo active transport across the CNS. Other properties (size, molecular weight, parti- tion coefficient, molecular flexibility (rotational bonding), solubility, polar surface, polarizability, bioavailability) are also factors that can affect the transport of an organic molecule to cross the BBB [5, 6]. Pain killers and mind-changers possess tre- mendous chemical diversity and yet reach their target(s) in the brain. The question is, “What physi- cal and medicinal-chemical characteristics do they possess to induce their various activities: pain kill- ers for the molecules of Mercy and mind changers for the molecules of Mysticism?” The most known molecules belonging to the group of the Molecules of Mysticism are the can- nabinoids (hashish, marihuana) extracted from Cannabis sativa, which are the oldest and most broadly occurring hallucinogens. Cannabis ranks second after opium as the most widely used mind-altering drug today. The most active ingre- dient of cannabinoids is D9-tetrahydrocannabi- nol (THC). In the late 1960s, researchers learned that there were specific areas in the brain con- trolling pain [7 – 9]. As for psychedelic drugs, hal- lucinogenic compounds, such as D1-Tetrahydro- cannabinol, Psylocibin, and LSD, exert their pri- mary effects through activating serotonin 5-HT2A receptors found predominantly in cortical re- gions [10]. The question that arises at the level of chemical structures and physicochemical pro- perties is, “How can the molecules of the group of pain killers be differentiated from those of mind- changers, taking into account that these two groups of compounds must penetrate the blood- brain barrier to reach their targets at the CNS level?” To answer this question, 23 drugs (US FDA approved or/and European marketing authoriza- tion) most prescribed for the treatment of pain (the Molecules of Mercy) and 18 molecules of well- known psychedelic drugs used for recreational purposes (the Molecules of Mysticism) and/or for mental disorders are included in this study. The physicochemical characteristics of these 41 mo- lecules could be found in DrugBank Online data, offered to the public as a free-to-access resource [11]. For each drug, 11 representative structur- al physicochemical parameters were considered: Molecular weight (MW), Chemical formula, Wa- ter solubility (mg mL-1), log P, log S, Hydrogen acceptor count, Hydrogen donor count, Rotatable bond count, Polar surface area (Å2), Polarizability (Å3), Bioavailability. Table 1 and Table 2 show the values of the physicochemical parameters for each drug belon- ging to both groups of drugs: 23 Molecules of Mer- cy (pain killers) and 19 Molecules of Mysticism (mind-changers), as well as their compliance with the Lipinski’s rule (Rule of five), Ghose filter, Veber’s rule, and MDDR-like rule. Notes to the descriptors that appear in Tables 1 and 2 are given below: MW – the molecular weight in g mol–1. Water Solubility in mg mL–1. LogP – the octa- nol-water partition coefficient [12]. LogS – the common solubility unit corresponding to the 10-based logarithm of the water solubility of a mo- lecule measured in mol L–1. HA – the number of hydrogen bond acceptors. HD – the number of hydrogen bond donors. Rotatable bonds – the number of single bonds which can freely rotate around their axis [13]. Bioavailability – repre- senting the fraction (F) of the administered dose ISSN 2308-8303 (Print) / 2518-1548 (Online) 6 Журнал органічної та фармацевтичної хімії 2025, 23 (1) Ta bl e 1. M ol ec ul es o f M er cy (p ai n ki lle rs ) № Ge ne ric n am es M W Ch em ic al fo rm ul a Water solubility, a mg mL–1 Lo g Pa Lo g Sa H Aa H Da Rotatable bondsa Bioavailabilitya Polar surface areaa Polarizabilitya Lipinskis ruleb (Rule of five) Ghose ruleb Vebers ruleb MDDR-like ruleb 1 Sa lic yl ic a ci d 18 0 C 9H 8O 4 10 1. 2 - 3 1 3 1 63 .6 7. 1 Ye s Ye s N o N o 2 Co de in e 29 9 C 18 H 21 N O 3 0. 57 1. 24 -2 .7 4 1 1 1 41 .9 3 31 .9 Ye s Ye s N o N o 3 Bu pr en or ph in e 46 7 C 29 H 41 N O 4 0. 01 7 4. 53 -4 .4 5 2 5 1 65 .0 7 53 .3 5 Ye s N o N o N o 4 M et ha do ne 30 9 C 21 H 27 N O 0. 00 6 4. 14 -4 .7 2 0 7 1 20 .3 1 36 .2 8 Ye s N o N o N o 5 N al or ph in e 31 1 C 19 H 21 N O 3 1. 36 1. 55 -2 .4 4 2 2 1 52 .9 3 33 .3 Ye s Ye s N o N o 6 Ce le co xi b 38 1 C 17 H 14 F 3N 3O 2S 0. 00 5 3. 99 -2 .7 3 1 4 1 59 .3 26 .6 7 Ye s Ye s N o N o 7 Ib up ro fe n 20 6 C 13 H 18 O 2 0. 07 0. 3. 5 -3 .5 2 1 4 1 37 .3 23 .7 6 Ye s Ye s Ye s N o 8 N ap ro xe n 26 0 C 14 H 14 O 3 0. 05 1 3. 29 -3 .6 3 3 1 1 46 .5 3 24 .8 Ye s Ye s N o N o 9 Pa ra ce ta m ol 15 1 C 8H 9N O 2 4. 15 0. 51 -1 .1 6 2 2 1 1 49 .3 3 15 .5 2 Ye s N o N o N o 10 Pr eg ab al in 15 9 C 8H 17 N O 2 11 .3 -1 .4 -1 .2 3 2 5 1 66 .3 2 18 .0 8 Ye s N o N o N o 11 Di cl of en ac 29 6 C 14 H 11 C l 2N 20 0. 00 45 4. 98 -4 .8 3 2 4 1 49 .3 3 27 .9 3 Ye s Ye s N o N o 12 O xy co do ne 31 5 C 18 H 21 N O 4 5. 59 . 1. 04 -1 .8 5 1 1 1 59 32 .7 9 Ye s Ye s N o N o 13 Ca rb am az ep in e 23 6 C 15 H 12 N 2O 0. 15 2 2. 1 -3 .2 1 1 0 1 46 .3 3 25 Ye s Ye s N o N o 14 Am itr ip ty lin e 27 7 C 20 H 23 N 0. 00 45 5. 1 -4 .8 1 0 3 1 3. 24 33 .7 4 Ye s Ye s N o N o 15 Ca ps ai ci n 30 5 C 14 H 27 N O 3 3. 75 - 3 2 9 1 58 .5 6 36 .3 2 Ye s Ye s N o N o 16 M el ox ic am 35 1 C 14 H 13 N 3O 4S 2 0. 15 4 2. 28 -3 .4 5 4 2 1 99 .6 34 .2 5 Ye s Ye s N o N o 17 Pr ed ni so lo ne 36 0 C 21 H 28 O 50 0. 23 90 1. 66 -3 .2 5 3 2 4 94 .8 3 38 .6 9 Ye s Ye s N o N o 18 M ep er id in e 24 7 C 15 H 21 N O 2 1. 11 2. 9 -2 .4 2 0 4 1 29 .5 4 28 .0 9 Ye s Ye s N o N o 19 Bu ta lb ita l 22 4 C 11 H 16 N 2O 3 2. 23 . 1. 47 -2 3 2 4 1 75 .2 7 22 .4 3 Ye s Ye s N o N o 20 N al tr ex on e 34 1 C 20 H 23 N O 4 3. 07 2. 07 -2 5 2 2 1 70 36 .0 3 Ye s Ye s N o N o 21 Ga ba pe nt in 17 1 C 9H 17 N O 2 4. 34 - 1 .9 -1 .6 3 2 3 1 63 .3 2 18 .9 2 Ye s Ye s N o N o 22 M or ph in e 28 5 C 17 H 19 N O 3 0. 14 9 0. 9 -1 .4 4 2 0 1 52 .9 3 29 .9 4 Ye s Ye s N o N o 23 Fe nt an yl 33 6 C 22 H 28 N 2O 0. 02 4 4. 12 -4 .2 2 0 6 1 23 .5 5 30 .8 9 Ye s Ye s Ye s Ye s N ot es : a R ep or te d Va lu es (W at er so lu bi lit y, lo g P, lo g S, H A, H D, R ot at ab le b on ds , B io av ai la bi lit y, P ol ar su rf ac e ar ea , P ol ar iza bi lit y) a re p re di ct ed v al ue s t hr ou gh th e AL O GP S 2. 1 pr og ra m ; b A ns w er s ( Ye s o r N ot ) a ss oc ia te d w ith th e ru le s o f F iv e, G ho se fi lte r, Ve be r a nd M DD R- lik e, a re g iv en a cc or di ng to D ru gB an k da ta ba se re co m m en da tio ns . ISSN 2308-8303 (Print) / 2518-1548 (Online) 7 Journal of Organic and Pharmaceutical Chemistry 2025, 23 (1) Ta bl e 2. M ol ec ul es o f M ys tic ism (m in d- ch an ge rs ) № Ge ne ric n am es M W Ch em ic al fo rm ul a Water solubility, a mg mL-1 Lo g Pa Lo g Sa H Aa H Da Rotatable bondsa Bioavailabilitya Polar surface area a Polarizabilitya Lipinski’s ruleb (Rule of five) Ghose ruleb Veber`s ruleb MDDR-like ruleb 1 He ro in 36 9 C 21 H 23 N O 5 0. 26 6 2. 3 -3 .1 4 0 0 1 65 .0 7 38 .1 9 Ye s Ye s N o N o 2 Co ca in e 30 3 C 17 H 21 N O 4 5. 03 1. 97 -1 8 3 0 5 1 55 .8 4 32 .0 2 Ye s Ye s N o N o 3 Er go ta m in e 58 1 C 33 H 35 N 5O 5 0. 23 3 2. 95 -3 .4 6 3 4 1 11 8. 21 62 .2 3 N o N o N o N o 4 LS D 32 3 C 20 H 25 N 3O 0. 27 3. 3 - 2 1 3 1 39 .3 4 37 .5 4 Ye s Ye s Ye s N o 5 M es ca lin e 21 1 C 11 H 17 N O 3 1. 0 0. 78 - 4 2 2 1 - - Ye s - - 6 Am ph et am in e 13 5 C 9H 13 N 1. 74 1. 85 -1 .9 1 1 2 1 26 .0 2 16 .1 7 Ye s N o Ye s N o 7 Ps yl oc ib in 28 4 C 12 H 17 N 2O 4P - 1. 24 - 4 3 5 1 85 .7 9 - Ye s - N o N o 8 N ik et ha m id e 17 8 C 10 H 14 N 2O 10 9. 0 0. 83 -0 .2 1 2 0 3 1 33 .2 19 .5 6 Ye s Ye s Ye s N o 9 Se ro to ni n 17 6 C 10 H 12 N 2O 2. 5 0. 56 -1 .8 2 3 2 1 62 .0 4 19 .3 1 Ye s Ye s N o N o 10 Ep in ep hr in e 18 3 C 9H 13 N O 3 0. 1 -0 .8 2 -0 .9 9 4 4 3 1 77 .7 2 19 .0 4 Ye s N o N o N o 11 Ph en et hy la m in e 12 1 C 8H 11 N 2. 19 1. 41 -1 .7 1 1 2 1 26 02 14 .3 6 Ye s N o Ye s N o 12 M et ha m ph et am in e 14 9 C 10 H 15 N 0. 92 8 2. 23 -2 .2 1 1 3 1 12 .0 3 18 .0 4 Ye s N o Ye s N o 13 Bu fo te ni ne 20 4 C 12 H 16 N 2O 3. 2 2. 04 -1 .8 2 2 3 1 39 .2 6 23 .2 9 Ye s Ye s Ye s N o 14 Te tr ah yd ro ca nn ab in ol 31 4 C 21 H 30 O 2 0. 00 26 7. 29 -5 .1 2 1 4 1 29 .4 6 38 .9 6 N o N o Ye s N o 15 M et hy lp he ni da te 23 3 C 14 H 19 N O 2 0. 18 2 1. 47 -2 .1 2 1 4 1 38 .3 3 25 .9 1 Ye s Ye s Ye s N o 16 Ca th in on e 14 9 C 9H 11 N O 2. 46 0. 51 -1 .8 2 1 2 1 43 .0 9 16 .2 8 Ye s N o N o N o 22 M or ph in e 28 5 C 17 H 19 N O 3 0. 14 9 0. 9 -1 .4 4 2 0 1 52 .9 3 29 .9 4 Ye s Ye s N o N o 23 Fe nt an yl 33 6 C 22 H 28 N 2O 0. 02 4 4. 12 -4 .2 2 0 6 1 23 .5 5 39 .8 9 Ye s Ye s Ye s Ye s N ot es : a R ep or te d Va lu es (W at er so lu bi lit y, lo g P, lo g S, H A, H D, R ot at ab le b on ds , B io av ai la bi lit y, P ol ar su rf ac e ar ea , P ol ar iza bi lit y) a re p re di ct ed v al ue s t hr ou gh th e AL O GP S 2. 1 pr og ra m ; b A ns w er s ( Ye s o r N ot ) a ss oc ia te d w ith th e ru le s o f F iv e, G ho se fi lte r, Ve be r a nd M DD R- lik e, a re g iv en a cc or di ng to D ru gB an k da ta ba se re co m m en da tio ns . ISSN 2308-8303 (Print) / 2518-1548 (Online) 8 Журнал органічної та фармацевтичної хімії 2025, 23 (1) of a xenobiotic that reaches the systemic circu- lation, measured on a continuous range from 0 to 1 [14]. Polar Surface Area (PSA) – defined as the surface sum over all polar atoms or mol- ecules, primarily oxygen and nitrogen, includ- ing also their attached hydrogen atoms [15, 16]. Polarizability – determines the response of the susceptibility of a molecule to an approaching charge. Larger molecules, atoms, or ions are more polarizable than smaller objects. Polarizability is expressed as the polarizability volume with units in Å3 = 10–24 cm3 [17, 18]. Rule of Five (Lipinski’s rule) – not more than 5 hydrogen bond donors; not more than 10 hydrogen bond acceptors; the molecular mass less than 500 Da [19]. Ghose Filter – the partition coefficient LogP from −0.4 to +5.6; the molecular refractivity from 40 to 130; the molecular weight from 180 to 480; the num- ber of atoms from 20 to 70 (includes H-bond do- nors [e.g., OHs and NHs] and H-bond acceptors [e.g., Ns and Os]) [20]. Veber’s rule – 10 or fe- wer rotatable bonds and the polar surface area equal to or less than 140 Å2 or 12 or fewer H-bond donors and acceptors [21]. MDDR-like rule – the rule-of-five test cannot be used to discriminate be- tween drugs and non-drugs. Descriptors used for the MDDR-like rule are the number of rings, the number of rigid bonds, and the number of rotata- ble bonds. The probability of finding a “druglike” compound is higher in the ranges: No. of rings ≥ 3, No. of rigid bonds ≥ 18, No. of rotatable bonds ≥ 6, while the probability of finding a ‘nondrug-like’ compound is higher in the ranges: No. of rings ≤ 2, No. of rigid bonds ≤ 17, No. of rotatable bonds ≤ 5 [22, 23]. Table 3 shows the average values of all the physicochemical parameters listed in Tables 1 and 2 related to both groups of drugs: Pain kill- ers and Mind-changers. ■ Discussion A careful analysis of the reported values allows us to determine what are the physicochemical properties that support the ability of these CNS drugs to act as pain killers or pain relievers and what are the physicochemical parameters that in- duce a mind-changer effect (psychedelic activity) in this group of drugs. Let us first recall that all the values of the physicochemical parameters con- sidered came from the same database, the Drug Bank, which is accessible freely online. All the molecules cited in this manuscript are used in clinical practice, mainly as pain killers, and are therefore approved by the FDA; other substances in the group of mind-changers are used in clinical practice, while others are classified as prohibited and non-commercial. It is known that all the molecules analyzed act at the CNS level, which means that all these drugs must penetra- te the blood-brain barrier. The analysis of the physicochemical parameters associated with each of the two groups – pain killers and mind-changer compounds – reveals differences in the average values of certain parameters. As can be seen from Table 3, the molecular weight, solubility, Log P, and log S values for the mind changer drugs are lower than for pain killers. On the contrary, the values of polarizability, po- lar surface area, hydrogen acceptor count, and hydrogen donor count of the pain killers are higher than those of the mind-changer drugs. From the results presented in Table 3, the following conclusions can be drawn: • most of the drugs belonging to both groups, the Molecules of Mercy or the Molecules of Mysticism, corresponded to the Lipinski’s rule as indicated in Tables 1 and 2; • 9 of 23 compounds of the Mysticism group sa- tisfy the Veber’s rule, while only 2 of 23 com- pounds of the Mercy group satisfy this rule; • the majority of the drugs (19/21) related to drugs of Mercy comply with the Ghose filter Table 3. The average values of all the physicochemical values related to both groups of drugs No. Physicochemical properties The Molecules of Mysticism (mind-changers) The Molecules of Mercy (pain killers) 1 MW 263.8 192.88 2 Solubility (mg/ml) 4.37 0.96 3 Log P 2.28 1.55 4 Log S -1.3 -2.17 5 HA 2.56 (between 2 and 3) 3.2 (between 3 and 4) 6 HD 1.2 (between 1 and 2) 1.3 (between 1 and 2) 7 Rotatable bonds 3 3 8 Polar Surface Area 30.58 54.14 9 Polarizability 29.01 31.51 10 Bioavailability 1 1 11 Rule of Five Yes (18/18) Yes (23/23) 12 Ghose Filter Yes (9/17) Yes (19/23) 13 Veber’s rule Yes (9/17) Yes (2/23) 14 MDDR-like rule Yes (2/18) Yes (0/23) Note: Values provided in Table 3 correspond to the mean ones calculated based on data from Tables 1 and 2 ISSN 2308-8303 (Print) / 2518-1548 (Online) 9 Journal of Organic and Pharmaceutical Chemistry 2025, 23 (1) rule, while only half of drugs of Mysticism comply with this rule; • most of the drugs of these two groups do not support the MDDR-like rules. Based on the data presented in Tables 1, 2, and 3, the development and synthesis of molecu- les for the treatment of pain in the CNS, in par- ticular for end-of-life care, requires a targeted approach. Chemists developing new pain killers or improving existing ones through molecular modifications should ensure that the physico- chemical properties of these molecules meet the criteria set out in Table 3. For Molecules of Mercy (pain killers), these new structures will represent pharmacological profi- les that would limit the side effects often asso- ciated with taking active painkiller ingredients (morphine and related analogs), mainly addic- tion effects. As indicated in Table 3, mind- changing drugs that act on the psyche (anxiety, depression) present physicochemical criteria sig- nificantly different from those of more specific molecules to combat pain. ■ Conclusion When designing new CNS drugs, it is necessa- ry to maintain a balance between physical and chemical requirements and achieve the best com- promises in properties depending on the target therapeutic effect – pain killers or mind-changers. While all CNS drugs (41 compounds), pain killers, and mind-changers involved in this study comply well with the Lipinski’s rule, it can be noted that pain killers mostly comply with the Ghose filter conditions, but do not satisfy the Veber’s rule. In contrast, only half of the mind-changer drugs agree with the Veber’s rule and satisfy the Ghose filter conditions. This observation indicates that other physicochemical parameters, such as polar surface area, polarizability, and flexibility, are im- portant parameters that can be manipulated by medical chemists involved in the CNS drug de- sign in order to modulate or improve the phar- macological effect of a new CNS drug depending on the desired target effect: pain reliever or mind changer activities. Of course, since we have fo- cused only on approved or natural, well-known drugs that ensure the BBB penetration, the con- clusions presented are restrictive. They could only be applied to drugs that satisfied the condition of the BBB penetration in order to orient the de- sired effect to the pain reliever effect rather than the mind changer effect. These results can be of in- terest since addictive psychedelic effects are often associated with the use of pain reliever drugs. ■ Acknowledgments CNRS-Aix Marseille University and Marseille Institute for Biology of Development (IBDM), director Dr. L. Kodjabachian, are greatly ac- knowledged for the facilities offered and finan- cial support. ■ References 1. Goodman, M.; Morehouse, F. Organic Molecules in Action; Gordon & Breach Publishing Group, 1973. 2. Painkillers and Prostaglandins. Nat. Struct. Mol. Biol. 2003, 10 (4), 233. https://doi.org/10.1038/nsb0403-233. 3. Kuteykin-Teplykanov K. Molecules of Mysticism: Pharmacology Meets Anthropology. Open foundation ICPR conference, October 24, 2010. Amsterdam University. 4. Sanders, J. W.; Zijlmans, J. Moving Past Mysticism in Psychedelic Science. ACS Pharmacol. Transl. Sci. 2021, 4 (3), 1253 – 1255. https://doi.org/10.1021/acsptsci.1c00097. 5. Pajouhesh, H.; Lenz, G. R. Medicinal Chemical Properties of Successful Central Nervous System Drugs. NeuroRX 2005, 2 (4), 541 – 553. https://doi.org/10.1602/neurorx.2.4.541. 6. Rankovic, Z. CNS Drug Design: Balancing Physicochemical Properties for Optimal Brain Exposure. J. Med. 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The Fundamental Role of Flexibility on the Strength of Molecular Binding. Soft Matter 2012, 8 (23), 6385. https://doi.org/10.1039/c2sm25160d. 15. Davis, J. L. Pharmacologic Principles. Equine Internal Medicine 2018, 4, 79 – 137. https://doi.org/10.1016/b978-0-323-44329-6.00002-4. 16. Ertl, P.; Rohde, B.; Selzer, P. Fast Calculation of Molecular Polar Surface Area as a Sum of Fragment-Based Contributions and Its Applica- tion to the Prediction of Drug Transport Properties. J. Med. Chem. 2000, 43 (20), 3714 – 3717. https://doi.org/10.1021/jm000942e. 17. Hitchcock, S. A.; Pennington, L. D. Structure−Brain Exposure Relationships. J. Med. Chem. 2006, 49 (26), 7559 – 7583. https://doi.org/10.1021/jm060642i. 18. Daintith, J. A Dictionary of Chemistry; Oxford University Press, 2008. https://doi.org/10.1093/acref/9780199204632.001.0001. 19. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Adv. Drug Delivery Rev. 1997, 23 (1 – 3), 3 – 25. https://doi.org/10.1016/s0169-409x(96)00423-1. 20. Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. 1. A Qualitative and Quantitative Characterization of Known Drug Databases. J. Comb. Chem. 1999, 1 (1), 55 – 68. https://doi.org/10.1021/cc9800071. 21. Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D. Molecular Properties That Influence the Oral Bioavail- ability of Drug Candidates. J. Med. Chem. 2002, 45 (12), 2615 – 2623. https://doi.org/10.1021/jm020017n. 22. Oprea, T. I. Property distribution of drug-related chemical databases. J. Comput.-Aided Mol. Des. 2000, 14 (3), 251 – 264. https://doi.org/10.1023/a:1008130001697. 23. Schneider, G. Automating Drug Discovery. Nat. Rev. Drug Discovery 2017, 17 (2), 97 – 113. https://doi.org/10.1038/nrd.2017.232. Information about the author: Jean-Louis Kraus, PhD, graduated from the Université de Bretagne Occidentale, France. After a post-doc at McGill University (Montreal, Canada), he joined the Université d’Avignon et des Pays du Vaucluse, as a chemistry professor. Actually, he is emeritus professor at Aix-Marseille University, Marseille, France. (Institut de Biologie du Développement, Marseille). His research interests are medicinal and pharmaceutical chemistry. He is co-founder of Trophos, a successful biotechnology start-up, with the discovery of olesoxime drug.
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spelling	oai:ojs.journals.uran.ua:article-3218602026-08-23T15:25:30Z Balancing Physicochemical Properties between the Molecules of Mercy (Non-Addictive Drugs) and the Molecules of Mysticism (Often Addictive Drugs) Балансування фізико-хімічних властивостей між молекулами милосердя (неадиктивними препаратами) і молекулами містицизму (часто адиктивними препаратами) Kraus, Jean-Louis розробка препаратів для ЦНС анальгетики психоактивні препарати фізико-хімічні властивості терапевтичні препарати CNS-drugs discovery pain killers mind-changers physicochemical properties therapeutic drugs The fundamental physicochemical features of drugs acting on the central nervous system (CNS) determine their ability to penetrate the blood-brain barrier (BBB) and be active against the CNS activities. In this paper, we study two well-known groups of drugs used or prescribed by physicists to treat CNS disorders. One group of drugs belongs to pain killers (the Molecules of Mercy), and the other group belongs to the mind-changers (the Molecules of Mysticism). These two groups of CNS drugs differ in a number of physicochemical parameters: molecular weight, lipophilicity, hydrogen bound acceptor count, hydrogen bond donor count, polar surface area, polarizability, flexibility, bioavailability, and their behavior (agreement or disagreement) related to specific structural conditions, in particular the Lipinski’s rule, Ghose filter, Veber’s rule, Multi-Drug Data Report (MDDR) criteria. In the study of 41 well-known drugs that affect the CNS (both approved or illegal), it has been found that painkillers that do not cause addiction have a physicochemical profile other than those of mind-changer drugs that are very often addictive. The features of physicochemical parameters associated with the profiles of “pain killer” and “mind-changer” drugs are discussed. Фундаментальні фізико-хімічні характеристики лікарських засобів, що діють на центральну нервову систему (ЦНС), визначають їхню здатність проникати через гематоенцефалічний бар’єр (ГЕБ) і проявляти активність щодо ЦНС. У цій роботі досліджено дві відомі групи препаратів, які застосовують для лікування розладів ЦНС. Перша група належить до анальгетиків (молекули милосердя), а друга – до психоактивних речовин (молекули містицизму). Ці дві групи лікарських засобів відрізняються за деякими фізико-хімічними параметрами: молекулярною масою, ліпофільністю, кількістю акцепторів і донорів водневого зв’язку, площею полярної поверхні, поляризованістю, «гнучкістю», біодоступністю, а також за відповідністю або невідповідністю певним структурним критеріям, зокрема правилу Ліпінські, фільтру Гоуза, правилу Вебера та критеріям Multi-Drug Data Report (MDDR). У ході дослідження 41 добре відомого лікарського засобу, що впливають на ЦНС (як затверджених, так і нелегальних), було виявлено, що анальгетики, які не викликають залежності, мають фізико-хімічний профіль, відмінний від профілю психоактивних речовин, які часто є адиктивними. У статті розглянуто особливості фізико-хімічних параметрів, пов’язані з профілями «анальгетичних препаратів» та «психоактивних препаратів». National University of Pharmacy 2025-02-14 Article Article Peer-reviewed Article application/pdf https://ophcj.nuph.edu.ua/article/view/321860 10.24959/ophcj.25.321860 Journal of Organic and Pharmaceutical Chemistry; Vol. 23 No. 1 (2025); 3-10 Журнал органической и фармацевтической химии; Том 23 № 1 (2025); 3-10 Журнал органічної та фармацевтичної хімії; Том 23 № 1 (2025); 3-10 2518-1548 2308-8303 en https://ophcj.nuph.edu.ua/article/view/321860/313631 Copyright (c) 2025 Jean-Louis Kraus http://creativecommons.org/licenses/by/4.0
spellingShingle	розробка препаратів для ЦНС анальгетики психоактивні препарати фізико-хімічні властивості терапевтичні препарати Kraus, Jean-Louis Балансування фізико-хімічних властивостей між молекулами милосердя (неадиктивними препаратами) і молекулами містицизму (часто адиктивними препаратами)
title	Балансування фізико-хімічних властивостей між молекулами милосердя (неадиктивними препаратами) і молекулами містицизму (часто адиктивними препаратами)
title_alt	Balancing Physicochemical Properties between the Molecules of Mercy (Non-Addictive Drugs) and the Molecules of Mysticism (Often Addictive Drugs)
title_full	Балансування фізико-хімічних властивостей між молекулами милосердя (неадиктивними препаратами) і молекулами містицизму (часто адиктивними препаратами)
title_fullStr	Балансування фізико-хімічних властивостей між молекулами милосердя (неадиктивними препаратами) і молекулами містицизму (часто адиктивними препаратами)
title_full_unstemmed	Балансування фізико-хімічних властивостей між молекулами милосердя (неадиктивними препаратами) і молекулами містицизму (часто адиктивними препаратами)
title_short	Балансування фізико-хімічних властивостей між молекулами милосердя (неадиктивними препаратами) і молекулами містицизму (часто адиктивними препаратами)
title_sort	балансування фізико-хімічних властивостей між молекулами милосердя (неадиктивними препаратами) і молекулами містицизму (часто адиктивними препаратами)
topic	розробка препаратів для ЦНС анальгетики психоактивні препарати фізико-хімічні властивості терапевтичні препарати
topic_facet	розробка препаратів для ЦНС анальгетики психоактивні препарати фізико-хімічні властивості терапевтичні препарати CNS-drugs discovery pain killers mind-changers physicochemical properties therapeutic drugs
url	https://ophcj.nuph.edu.ua/article/view/321860
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Балансування фізико-хімічних властивостей між молекулами милосердя (неадиктивними препаратами) і молекулами містицизму (часто адиктивними препаратами)

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