H]phosphatydilinositol). All drugs stimulated h5-HT 1A receptors with efficacies (compared with 5-HT, 100%) ranging from modest (apomorphine, 35%) to high (cabergoline, 93%). At h5-HT 1B receptors, efficacies varied from mild (terguride, 37%) to marked (cabergoline, 102%) and potencies were modest (pEC 50 values of 5.8 -7.6): h5-HT 1D sites were activated with a similar range of efficacies and greater potency (7.1-8.5). Piribedil and apomorphine were inactive at h5-HT 1B and h5-HT 1D receptors. At h5-HT 2A receptors, terguride, lisuride, bromocriptine, cabergoline, and pergolide displayed potent (7.6 -8.8) agonist properties (49 -103%), whereas apomorphine and roxindole were antagonists and piribedil was inactive. Only pergolide (113%/8.2) and cabergoline (123%/8.6) displayed pronounced agonist properties at h5-HT 2B receptors. At 5-HT 2C receptors, lisuride, bromocriptine, pergolide, and cabergoline were efficacious (75-96%) agonists, apomorphine and terguride were antagonists, and piribedil was inactive. MDL100,907 and SB242,084, selective antagonists at 5-HT 2A and 5-HT 2C receptors, respectively, abolished these actions of pergolide, cabergoline, and bromocriptine. In conclusion, antiparkinson agents display markedly different patterns of agonist and antagonist properties at multiple 5-HT receptor subtypes. Although all show modest (agonist) activity at 5-HT 1A sites, their contrasting actions at 5-HT 2A and 5-HT 2C sites may be of particular significance to their functional profiles in vivo.

SCH23390 is a potent and high efficacy agonist at h5-HT2C receptors. Activation of 5-HT2C receptors by SCH23390 may contribute to its functional properties both in animals and in humans.

Employing a novel, rapid and sensitive method for evaluation of phospholipase C (PLC) activity, the present study characterized the actions of diverse agonists and antagonists at human (h)5-HT2C receptors expressed in Chinese Hamster Ovary (CHO) cells. In addition, affinities and efficacies at these sites were compared with those obtained at h5-HT2B receptors.5-HT elicited a robust and rapid reduction in levels of the pre-labelled, membrane-bound substrate of PLC, [3H]phosphatidylinositols ([3H]PI). The time-course of [3H]PI depletion paralleled that of [3H]inositol phosphate ([3H]IP) accumulation, as determined by conventional anion exchange chromatography. Inactivation of h5-HT2C receptors with the alkylating agent, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), revealed a large receptor reserve, with half-maximal PLC activation induced by a concentration of 5-HT occupying only 5% of sites. In analogy to 5-HT ( Emax=100%), DOI, MK212 and mCPP, as well as the novel ligands, Ro600332, Ro600175 and BW723C86, showed "full" efficacy at h5-HT2C sites. Their efficacies were similar at h5-HT2B sites, with the exception of mCPP and MK212, which acted as partial agonists. Further, lisuride and Ro600869 behaved as partial agonists and antagonists at h5-HT2C and h5-HT2B receptors, respectively. As concerns functional selectivity (potency for induction of [3H]PI depletion), only Ro600175 preferentially activated h5-HT2B sites. In contrast, Ro600332 preferentially activated h5-HT2C receptors. Amongst antagonists, RS102221 and SB242084 displayed a marked preference for h5-HT2C sites, whereas LY266097, S33526 and SB204741 behaved as selective antagonists at h5-HT2B receptors. At both h5-HT2C and h5-HT2B receptors, antagonist potency (p Kb) and binding affinity (p Ki) were highly correlated. In conclusion, this rapid and innovative method for determination of PLC activity permitted characterization of an extensive range of novel ligands at h5-HT2C receptors. Although several antagonists clearly differentiated h5-HT2C from h5-HT2B receptors under these conditions, highly selective agonists remain to be identified.

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