Mini Reviews in Medicinal Chemistry - Volume 5, Issue 6, 2005

Cell-surface G protein-coupled receptors (GPCRs) constitute nearly 5% of the human genome, making them the largest superfamily of all receptor proteins. Approximately 300 - 350 of a total of 700 - 1000 GPCRs are the “non-sensory” GPCRs, which represent the main drug targets for the majority of medicines currently available. In particular, the “rhodopsin-like” Class I (Family A) GPCRs are pre-eminent therapeutic targets. Given that half of the non-sensory GPCRs are “orphan” receptors, it is evident that GPCR-based drug discovery will remain a vital practice well into the new millennium. The classic approach to GPCR-based drug discovery has long been the optimization of lead molecules to target the “orthosteric” site on the receptor, i.e., the site that is recognized by the endogenous agonist for that receptor. Orthosteric ligands have traditionally been classed as agonists, neutral (competitive) antagonists and inverse agonists. However, it is now becoming recognized that many GPCRs possess additional, “allosteric”, binding sites that modulate receptor activity through conformational changes transmitted to the orthosteric site or directly to effector coupling sites. The structure-activity relationships that govern orthosteric effects do not apply to allosteric binding sites, leading to a greater scope for ligand fishing in the chemical space encompassing biologically active molecules. Furthermore, allosteric modulator ligands of GPCRs possess a number of advantages over classic orthosteric drugs, including a greater potential for receptor selectivity and a higher safety in overdose due to a ceiling level to their effect. Despite their theoretical advantages, allosteric interactions are more complex than orthosteric interactions, and the manifestations of allosterism at GPCRs are many and varied. Thus, the successful detection, validation and quantification of allosteric phenomena at GPCRs require modifications of standard approaches used to screen for orthosteric ligands. The current paucity of allosteric modulators in the known population of biologically active molecules is likely due to the fact that classic high-throughput screens are biased towards the detection of orthosteric ligands, but functional assays have now overtaken radioligand-binding assays as the high-throughput method of choice, and allosteric ligands that have minimal effects on orthosteric binding are being discovered through their effects on receptor signalling. Nevertheless, the optimal detection of novel allosteric ligands requires the combination of both standard functional and modulator-optimized binding assays. This issue of Mini-Reviews in Medicinal Chemistry contains three reviews from international leaders in the study of Class I GPCR allosterism. Birdsall and Lazareno provide an excellent overview on the methodological approaches and pitfalls associated with the detection and quantification of allosteric modulator ligands, using the muscarinic acetylcholine receptors as a prototypical example. A structure-activity focus is provided in the review by Gao, Kim, IJzerman and Jacobson on allosteric modulators of the adenosine family of receptors. Finally, Schetz outlines the various modes of modulation of the dopamine family of GPCRs. These reviews are particularly timely, as there are now a number of allosteric modulators in clinical trials with many more likely to eventuate from current drug discovery programs. I am extremely grateful to the contributors for ensuring that this issue will become a valuable resource to others in the growing field of GPCR allosterism.

The evaluation of allosteric ligands at muscarinic receptors is discussed in terms of the ability of the experimental data to be interpreted by the allosteric ternary complex model. The compilation of useful SAR information of allosteric ligands is not simple, especially for muscarinic receptors, where there are multiple allosteric sites and complex interactions.

Allosteric modulators for adenosine receptors (ARs) are of an increasing interest and may have potential therapeutic advantage over orthosteric ligands. Benzoylthiophene derivatives (including PD 81,723), 2-aminothiazolium salts, and related allosteric modulators of the A1 AR have been studied. The benzoylthiophene derivatives were demonstrated to be selective enhancers for the A1 AR, with little or no effect on other subtypes of ARs. Allosteric modulation of the A2A AR has also been reported. A3 allosteric enhancers may be predicted to be useful against ischemic conditions. We have recently characterized two classes of A3 AR allosteric modulators: 3-(2-pyridinyl)isoquinolines (e.g. VUF5455) and 1H-imidazo-[4,5- c]quinolin-4-amines (e.g. DU124183), which selectively decreased the agonist dissociation rate at the human A3AR but not at A1 and A2A ARs. DU124183 left-shifted the agonist conc.-response curve for inhibition of forskolin-stimulated cAMP accumulation in intact cells expressing the human A3AR with up to 30% potentiation of the maximal efficacy. The increased potency of A3 agonists was evident only in the presence of an A3 antagonist, since VUF5455 and DU124183 also antagonized, i.e. displaced binding at the orthosteric site, with Ki values of 1.68 and 0.82 μM, respectively. A3AR mutagenesis studies implicated F1825.43 and N2747.45 in the action of the enhancers and was interpreted using a rhodopsin-based A3AR molecular model, suggesting multiple binding modes. Amiloride analogues, SCH-202676 (N-(2,3-diphenyl-1,2,4-thiadiazol- 5(2H)-ylidene)methanamine), and sodium ions were demonstrated to be common allosteric modulators for at least three subtypes (A1, A2A, and A3) of ARs.

Allosteric modulators allow for the fine-tuning of receptor responses to endogenous neurotransmitters and exogenous therapeutic agents. Different types of allosteric modulation of dopamine receptors are discussed as well as the significance of such modulation in the control of normal biological processes and in the treatment of disease.

During the last decade an increasing number of reports describe the roles of active oxygen species in the development or exacerbation of various kinds of diseases. Antioxidants are of great interest because of their involvement in important biological and industrial processes. They have been found to possess anticancer, anti-cardiovascular, anti-inflammatory and many other activities. Many attempts have been made to elucidate the QSAR of antioxidants by using different physicochemical parameters. Unfortunately the limited number of antioxidants and the unavailable σ Hammett values of complex substituents did not lead to significant results in regression analysis. The redox potentials are well correlated to the antioxidant activities. In this report we will attempt to collect and discuss all the published results concerning the QSAR research on natural and synthetic antioxidants compounds.

The migration of leukocytes from the blood stream to sites of infection is a key event in cellular immune response, mediated by multiple types of molecules including several adhesion receptors. The inhibition of adhesion receptors holds great promise for novel therapeutical strategies to treat chronic inflammatory disorders or autoimmune diseases. This review reports on recent advances in adhesion-based therapeutics and focuses on structural classification of selectin and integrin inhibitors.

One of the most important stages of the drug discovery process is the generation of lead compounds. Structure-activity relationships (SAR) are well-integrated in modern drug discovery and have been largely used for the finding of new leads, scaffold generation, the optimization of receptor or enzyme affinity, as well as of pharmacokinetic and physicochemical properties. This review highlights some SAR approaches that can be used to optimize leads through a continuous, multi-step process based on knowledge gained at each stage, thus exploiting SAR in the design of selective, potent, small-molecule drug candidates.

Since the introduction of (+)-tubocurarine into anaesthetic and surgical practice (1942), a number of non-depolarizing neuromuscular blocking agents (NMBs) with improved pharmacological properties have been developed during the last sixty years. However, after withdrawal of rapacuronium from clinical use, there is still a need for an ultra-short acting non-depolarizing muscle relaxant with rapid onset as substitution for the polarizing suxamethonium, which has several undesirable side-effects. In this paper, structure-activity relationships within four different series of NMBs (tetrahydroisoquinolinium, bistropinyl diester, aminosteroid, and amino peptide analogues) published in this millennium have been reviewed. The NMB properties of the most promising drug candidates from each series were discussed and compared to those of the already existing muscle relaxants.