| Abstract: |
Serotonin (5-liydroxytryptamine; 5-HT) is a neurotransmitter that mediates both excitatory and inhibitory processes in the mammalian central nervous system and ill the periphery. 5-HT mediates its diverse effects through interacting with a large family, of cell surface receptors. The explosive growth of the 5-HT superfamily of G-protein coupled receptors, achieved by radioligand binding and molecular cloning techniques, has continued to provide pharmaceutical research with new opportunities for drug discovery. To date, seven 5-HT receptor families (5-HTi to 5-HT7) are identified. At present, the 5-HT2 receptor family is comprised of three subtypes, namely 5-HT2A, 5-HT2ij, and 5-HT2c, which have been grouped in this same class on the basis” of molecular structure, signal transduction characteristics, and pharmacology. 5-HT2 receptors are of significant clinical interest because of their potential involvement in a variety of mental disorders and cardiovascular function. Sequence analysis reveals about 80% amino acid homology in the transmembrane domains of all three receptors and, therefore, there has been a paucity of ligands that show 5-HT2 subpopulation selectivity. The neuroleptic drug spiperone is one of the few agents that display considerable selectivity for 5-HT2A versus 5-HT2c receptors; however, it binds with appreciable affinity at 5-HT|A receptors and is highly potent at D2 receptors: In addition, spiperone is behaviorally disruptive to animals and, therefore, is not suitable for use in drug discrimination studies. AM I-193, the phenoxy analog of spiperone, is a newer ligand with improved 5-HT2A/5-HT2c selectivity.
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