Handbook of psychopharmacology

Years of cumulative research can result in the development of a clinically useful drug, providing either a cure for a particular disease or symptomatic relief from a physiological disorder. A lead compound with a desired pharmacological activity may have associated with it undesirable side effects, characteristics that limit its bioavailability, or structural features which adversely influence its metabolism and excretion from the body. Bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents. The concept of bioisosterism is often considered to be qualitative and intuitive.1 The prevalence of the use of bioisosteric replacements in drug design need not be emphasized. This topic has been reviewed in previous years.2-5 The objective of this review is to provide an overview of bioisosteres that incorporates sufficient detail to enable the reader to understand the concepts being delineated. While a few popular examples of the successful use of bioisosteres have been included, the George Patani graduated with a B.Pharm. in 1992 from the College of Pharmaceutical Sciences, Mangalore University at Manipal, India. In 1996, he received his M.S. in Pharmaceutical Science at Rutgers University under the direction of Professor Edmond J. LaVoie. He is presently pursuing graduate studies in pharmaceutics. His current research interests are focused on drug design and controlled drug delivery.

https://www.mch.estranky.sk/file/228/1996chemrev96-3147-76_bioisosterism.pdf

Bioisosterism: A Rational Approach in Drug Design.

Pharmacology of cannabinoid cb1 and cb2 receptors

Δ9-Tetrahydrocannabinol (Δ9-THC), the major psychoactive ingredient in preparations of Cannabis sativa (marijuana, hashish), elicits central nervous system (CNS) responses, including cognitive alterations and euphoria. These responses account for the abuse potential of cannabis, while other effects such as analgesia suggest potential medicinal applications. To study the role of the major known target of cannabinoids in the CNS, the CB1 cannabinoid receptor, we have produced a mouse strain with a disrupted CB1 gene. CB1 knockout mice appeared healthy and fertile, but they had a significantly increased mortality rate. They also displayed reduced locomotor activity, increased ring catalepsy, and hypoalgesia in hotplate and formalin tests. Δ9-THC-induced ring-catalepsy, hypomobility, and hypothermia were completely absent in CB1 mutant mice. In contrast, we still found Δ9-THC-induced analgesia in the tail-flick test and other behavioral (licking of the abdomen) and physiological (diarrhea) responses after Δ9-THC administration. Thus, most, but not all, CNS effects of Δ9-THC are mediated by the CB1 receptor.

https://www.pnas.org/content/pnas/96/10/5780.full.pdf

Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice

Cannabinoid receptors and pain.

It has been found that the previously inactive narcoticantagonist analgesics become active in the mouse tail-flick test in the presence of physostigmine. Physostigmine itself and the centrally acting cholinergic agent oxotremorine are potent inhibitors of this reflex. Naloxone, a pure narcotic antagonist, can block the effects of physostigmine and oxotremorine. The narcotic-antagonist analgesics also block the contractions of the isolated coaxially stimulated guinea-pig ileum. In a wide variety of narcotic antagonists, a high correlation has been found between the activity of these compounds in this test procedure and their potency as analgesics in man. These results are discussed in support of the hypothesis that cholinergic systems may be involved in the analgesic action of these drugs.

Narcotic-antagonist analgesics: interactions with cholinergic systems

THERE have been few reports concerning the chemistry and pharmacology of marijuana and its constituents1,2, and most investigators have studied the natural product or a crude extract. Mechoulam and co-workers3 isolated Δ9-tetrahydrocannabinol, which is believed to be the most active constituent of marijuana and has been shown to have marijuana-like activity in man4. Subsequently, Δ8-tetrahydrocannabinol was purified and now both isomers have been prepared synthetically and are available in small quantities for pharmacological experimentation. These substances are somewhat unique in that there are few agents which have such a profound effect on the central nervous system yet do not contain either a sulphur or nitrogen atom in the molecule. We report here some preliminary pharmacological results with pure synthetic Δ8 and Δ9-tetrahydrocannabinol (Δ9-THC), and also describe the effect of the insertion of a heterocyclic atom in ring C on the pharmacology of these agents. The nitrogen analogue of Δ9-THC (I in Fig. 1) was synthesized by Pars and co-workers5 and the sulphur analogue (II) by R. K. R. (unpublished data).

Pharmacology of some Marijuana Constituents and Two Heterocyclic Analogues

Various nitrogen analogs of delta6a,10a-tetrahydrocannabinol were synthesized by a general procedure described in an earlier communication. Minimum effective doses (MED50's) and lethal doses (LD50's) were determined by a modified Irwin mouse screen after iv administration of compounds in PEG 200. The most potent compounds were the propargyl (5t), allyl (5m), and chloroallyl (5o-q) derivatives. Overt behavioral effects (CNS depression, static ataxia, and hypersensitivity) of 5t and Roger Adams' carbocyclic analog (III) were found to be similar in the mouse, cat, dog, and monkey. Dichloroisoproterenol prevented and reversed many of the depressant effects of both III and 5t but had no effect on the ataxia produced by these compounds. In antinociceptive tests, 5t was active in the phenylquinone and Eddy hot-plate tests but was inactive in the tail-flick test.

Drugs derived from cannabinoids. 1. Nitrogen analogs, benzopyranopyridines and benzopyranopyrroles.

Delta1-Tetrahydrocannabinol, which is resinous and insoluble in water and therefore difficult to study pharmacologically, can be converted to a watersoluble derivative without loss of its biological activity. This has been achieved by preparing esters bearing a nitrogen moiety with the use of carbodiimide as the condensing agent. The availability of such water-soluble derivatives will allow the evaluation of Delta1-tetrahydrocannabinol in self-administration studies in monkeys for its addiction liability potential in man. This technique of water solubilization is also applicable to other compounds of chemical and biological significance.

Water-soluble derivatives of 1 -tetrahydrocannabinol.

Various basic esters of nitrogen (2) and carbocyclic (3 and 4) analogs of cannabinoids were synthesized using dicyclohexylcarbodiimide in methylene chloride. The compounds in the three series werw studied in selected pharmacological tests in mice, rats, dogs, and cats. It was shown that making the basic ester from the phenol retains biological activity and can lead to a greater selectivity of action, particularly the antinociceptive activity. The most interesting esters were 5, 6, 10, and 14 in the nitrogen analogs series and 19 and 20 in the carbocyclic series. Compound 5 was more potent than codeine in the writhing, hot-plate, and tail-flick tests and is at present undergoing clinical testing. Compound 20 was very potent in the mouse audiogenic seizure test and is of interest as an anticovulsant agent.

Harry G Pars

Papers

Narcotic-antagonist analgesics: interactions with cholinergic systems

Pharmacology of some Marijuana Constituents and Two Heterocyclic Analogues

Drugs derived from cannabinoids. 1. Nitrogen analogs, benzopyranopyridines and benzopyranopyrroles.

Water-soluble derivatives of 1 -tetrahydrocannabinol.

Drugs derived from cannabinoids. 2. Basic esters of nitrogen and carbocyclic analogs.