Receptors allosteric site

NMD A receptors are selectively activated by A/-methyl-D-aspartate (NMD A) (182). NMD A receptor activation also requires glycine or other co-agonist occupation of an allosteric site. NMDAR-1, -2A, -2B, -2C, and -2D are the five NMD A receptor subunits known. Two forms of NMDAR-1 are generated by alternative splicing. NMDAR-1 proteins form homomeric ionotropic receptors in expression systems and may do so m situ in the CNS. Functional responses, however, are markedly augmented by co-expression of a NMDAR-2 and NMDAR-1 subunits. The kinetic and pharmacological properties of the NMD A receptor are influenced by the particular subunit composition. 

It is useful to think of the allosteric binding not in terms of deformation of the receptor active site but rather as a lever to lock the receptor into a given conformation. 

The first and best-studied allosteric site on GPCRs is that on the muscarinic receptor [9,10,12,19,20]. For the five subtypes of these receptors that have been cloned and pharmacologically defined as Mi to M5, various agents have been identified that allosterically regulate selectively these... 

A growing number of other diverse compounds have also been shown to bind to an allosteric site on the muscarinic receptors. Among them are pirenzepine (highly selective for Mi receptor), lidocaine and verapamil (ion channel blockers), tacrine (anticholinesterase compound), batrachotoxin, and strychnine (glycine receptor antagonist) [25,31-35],... 

Waelbroek M. Identification of drugs competing with <5 -tubocurarine for an allosteric site on cardiac muscarinic receptors. Mol Pharmacol 1994 46 685-692. 

Howard MJ, Hughes RJ, Motulsky HJ, Mullen MD, Insel PA. Interactions of amiloride with alpha- and beta-adrenergic receptors amiloride reveals an allosteric site on alpha 2-adrenergic receptors. Mol Pharmacol 1987 32 53-58. 

Waelbroeck M, Robberecht P, De Neef P, Christophe J. Effects of verapamil on the binding properties of rat heart muscarinic receptors evidence for an allosteric site. Biochem Biophys Res Commun 1984 121 340-345. 

Guilarte TR, Miceli RC, Jett DA. 1995. Biochemical evidence of an interaction of lead at the zinc allosteric sites of the NMDA receptor complex effects of neuronal development. Neurotoxicology 16 63-71. 

The GABA-gated chloride ion channel is modulated by several classes of drugs that bind to allosteric sites on the receptor complex the benzodiazepines, barbiturates and related intravenous general anesthetics such as etomidate and propofol, as well as anesthetic steroids and endogenous neurosteroids. It appears that some types of GABAa receptor are directly enhanced by ethanol and volatile general anesthetics (Fig. 16-2) [7,8,20]. 

The first allosteric modulators discovered to act on AMPA/KA receptors were the plant lectins, including concanavalin A (ConA), that block receptor desensitization, probably through binding to Y-1 inked oligosaccharides (51,52). It was soon discovered that certain benzothiazides, such as diazoxide and cyclothiazide, also act on the same allosteric site controlling non-NMDA receptor desensitization (53-55). Interestingly, ConA and cyclothiazide show high selectivity for KA and AMPA receptors, respec-... 

Many natural compounds and drugs do not directly activate or inhibit a receptor process rather they bind to allosteric sites on the receptor protein to modulate the effects of the endogenous ligand. Examples of... 

Trankle, C., Andresen, I., Lambrecht, G., Mohr, K. M2 receptor binding of the selective antagonist AF-DX 384 possible involvement of the common allosteric site. Mol. Pharmacol. 1998, 53, 304-312... 

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