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.

Although cocaine binds to several sites in the brain, the biochemical receptor mechanism or mechanisms associated with its dependence producing properties are unknown. It is shown here that the potencies of cocaine-like drugs in self-administration studies correlate with their potencies in inhibiting [3H]mazindol binding to the dopamine transporters in the rat striatum, but not with their potencies in binding to a large number of other presynaptic and postsynaptic binding sites. Thus, the cocaine receptor related to substance abuse is proposed to be the one associated with dopamine uptake inhibition.

https://science.sciencemag.org/content/sci/237/4819/1219.full.pdf

Cocaine receptors on dopamine transporters are related to self-administration of cocaine

Regulation of noradrenaline release by presynaptic receptor systems.

The traditional receptor-stimulus model of agonism began with a description of drug action based on the law of mass action and has developed by a series of modifications, each accounting for new experimental evidence. By contrast, in this paper an approach to modelling agonism is taken that begins with the observation that experimental agonist-concentration effect, E/[A], curves are commonly hyperbolic and develops using the deduction that the relation between occupancy and effect must be hyperbolic if the law of mass action applies at the agonist-receptor level. The result is a general model that explicitly describes agonism by three parameters: an agonist-receptor dissociation constant, KA; the total receptor concentration, [R0]; and a parameter, KE, defining the transduction of agonist-receptor complex, AR, into pharmacological effect. The ratio, [R0]/KE, described here as the 'transducer ratio', tau, is a logical definition for the efficacy of an agonist in a system. The model may be extended to account for non-hyperbolic E/[A] curves with no loss of meaning. Analysis shows that an explicit formulation of the traditional receptor-stimulus model is one particular form of the general model but that it is not the simplest. An alternative model is proposed, representing the cognitive and transducer functions of a receptor, that describes agonist action with one fewer parameter than the traditional model. In addition, this model provides a chemical definition of intrinsic efficacy making this parameter experimentally accessible in principle. The alternative models are compared and contrasted with regard to their practical and conceptual utilities in experimental pharmacology.

Operational models of pharmacological agonism

A wide variety of tissues undergo a change of functional state on exposure to noradrenaline or adrenaline. Those molecular constituents of the effector cells of a tissue with which molecules of these catecholamines must first interact in order to produce a change of state — or response — of the tissue, are the so-called adrenoceptors (also commonly called adrenergic receptors). For convenience, we refer to noradrenaline, adrenaline and other agents which produce responses in tissues by interacting with adrenoceptors, as adrenergic agonists. An agent which specifically inhibits a response produced by an adrenergic agonist is referred to as adrenergic blocking agent or adrenergic antagonist.

The Classification of Adrenoceptors (Adrenergic Receptors). An Evaluation from the Standpoint of Receptor Theory

Molecular Geometry and Adrenergic Drug Activity

The experiments were designed to study the well-known pigment-dependent mydriatic effect of atropine in the eye. In vitro, relative to the accumulation of 3H-atropine by the nonpigmented rabbit iris, the pigmented iris accumulated high amounts of the drug. A nonpigmented tissue, stomch fundus strip, obtained from either albino or nonalbino animals, accumulated relatively low amounts of 3H-atropine. On repeated washings, the accumulated drug from the nonpigmented tissues was rapidly lost, T 1/2 of 14 minutes, while that accumulated by the pigmented iris was retained much longer. Although in vitro aqueous humor from serum-atropinesterase positive rabbits rapidly degraded atropine, extracts from irides of the same type of rabbit gave a single peak radioactivity, with Rf identical to the authentic atropine sulfate. The accumulation of 3H-atropine by pigmented human iris or pigment epithelium was similar to that observed for the pigmented rabbit iris. pA2 values of atropine from nonpigmented iris and from fundus strips varied between 8.58 and 8.88 with slope values close to 1. The pA2 value of atropine in pigmented iris was 8.82; at higher concentrations, atropine was less effective compared to the nonpigmented iris. In the pigmented iris, the lesser effectiveness of the drug at high concentration could be explained on the basis of accumulation of the drug by the pigment cell and its constituents. Thus, the free concentration of the drug in the vicinity of the muscarinic receptor will fall. The lesser concentration will give weaker muscarinic blockade in the pigmented iris. On repeated washing, the atropine blockade of the nonpigmented iris could be easily washed out while that in the pigmented iris was retained. In vivo, the relative T 1/2 for the duration of atropine mydriasis in rabbits were: albino atropinesterase-positive, 3.8 hours; nonalbino atropinesterase-positive, 12.4 hours; albino atropinesterase-negative is greater than or equal to 96 hours. Only the latter T 1/2 for the duration of atropine mydriasis is quite clear. The small magnitude of the mydriatic effect in humans is explained by the loss of free drug to the pigment cells and their constituents. The longer duration of mydriatic effect in the heavily pigmented eye is explained on the basis of slow release of the accumulated drug onto the muscarinic receptor.

Iris pigmentation and atropine mydriasis.

Steric Aspects of Adrenergic Drugs

Recently, we have described the binding of [?H]dihydroazapetine, a reversible a-adrenoceptor antagonist, to a crude membrane fraction from the rat vas deferens (Ruffolo, Miller & others, 1976a; Ruffolo, Fowble & others, 1976b). [3H]Dihydrozapetine binds to a site with many characteristics expected for the a-adrenoceptor. In particular, all a-adrenoreceptor antagonists, and those agonists of the imidazoline class, inhibited specific binding of [3H]dihydroazapetine with excellent correlation between affinity for the binding site and known affinity for the receptor. Direct-acting agonists of the phenethylamine class (i.e. structural analogues of noradrenaline), however, paradoxically increased binding. An allosteric effect was postulated to explain these results which are also consistent with the pharmacological experiments of Kalsner (1970, 1973). The differential effects between agonists of the phenethylamine and imidazoline classes with respect to [3H]dihydroazapetine binding, combined with the marked structural dissimilarities between the two classes, prompted us to propose that imidazolines interact at a different site on the receptor than the phenethylamines. A similar postulation involving different sites of interaction on the a-adrenoceptor for agonists and structurally dissimilar antagonists has been proposed by AriCns & Simonis (1964). We believe that our pharmacological experiments on receptor desensitization furnish evidence for the existence of different sites of interaction on the cr-adrenoceptor for agonists of the imidazoline and phenethylamine classes. The imidazoline agonists are relatively long-acting and produce receptor desensitization upon repeated administration (Mujic & van Rossum, 1965; Sanders, Miller & Patil, 1975). It was reasoned that if one common binding site, or mode of binding, existed for imidazolines and directly-acting phenethylamines, then desensitization of the a-adrenoceptor to an imidazoline would result in desensitization to other imidazolines as well as the phenethylamines. Conversely, if different sites of interaction were to exist, cross-desensitization between imidazolines and phenethylamines might not occur. It is believed that desensitization experiments may be useful in distinguishing between different receptors (Barsoum & Gaddum, 1935; Waud, 1968; Schild, 1973). The possibility exists, therefore, that the procedure may also discriminate between different sites of interaction on the same receptor protein. Vasa deferentia were isolated from male albino rats and mounted in constant temperature (37.5\") organ baths for recording isometric drug-induced contractions

Lack of cross‐desensitization between structurally dissimilar α‐adrenoceptor agonists

In melanocytes, the biosynthesis of L-dopa derived indole polymer, melanin, is accelerated by tyrosinase and related enzymes. The brown to black pigment is characterized by a stable free-radical property. In humans, a pigment dependent slow onset of ocular actions of ephedrine, atropine, cocaine, pilocarpine and related medications was observed. Extensive accumulation of drugs by melanin appears to be the most important factor governing the long term therapeutic/toxicological activities. Drugs crossing placental circulation are localized in the mouse fetal eye. Thus, drugs exhibit a high binding capacity for melanin containing tissues. Studies on synthetic melanin and melanin granules also indicated a high binding capacity of many therapeutic classes of drugs, including psychotropics. In addition to the liposoluble property of the molecule, there is a definite relationship between chemical structure and the affinity of drugs for melanin. For example, the affinity of chlorpromazine for melanin is ...

Popat N. Patil

Papers

Molecular Geometry and Adrenergic Drug Activity

Iris pigmentation and atropine mydriasis.

Steric Aspects of Adrenergic Drugs

Lack of cross‐desensitization between structurally dissimilar α‐adrenoceptor agonists

Relevance of drug-melanin interactions to ocular pharmacology and toxicology