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Pharmacological Analysis of the Novel, Rapid, and Potent Inactivation of the Human 5-Hydroxytryptamine₇ Receptor by Risperidone, 9-OH-Risperidone, and Other Inactivating Antagonists

Center for Neuropharmacology & Neuroscience, Albany Medical College, Albany, New York

In a previous publication, using human 5-hydroxytryptamine₇ (h5-HT₇) receptor-expressing human embryonic kidney (HEK) 293 cells, we reported the rapid, potent inactivation of the h5-HT₇ receptor stimulation of cAMP production by three antagonists: risperidone, 9-OH-risperidone, and methiothepin (Smith et al., 2006). To better understand the drug-receptor interaction producing the inactivation, we 1) expanded the list of inactivating drugs, 2) determined the inactivating potencies and efficacies by performing concentration-response experiments, and 3) determined the potencies and efficacies of the inactivators as irreversible binding site inhibitors. Three new drugs were found to fully inactivate the h5-HT₇ receptor: lisuride, bromocryptine, and metergoline. As inactivators, these drugs displayed potencies of 1, 80, and 321 nM, respectively. Pretreatment of 5-HT₇-expressing HEK cells with increasing concentrations of the inactivating drugs risperidone, 9-OH-risperidone, methiothepin, lisuride, bromocriptine, and metergoline potently inhibited radiolabeling of the h5-HT₇ receptor, with IC₅₀ values of 9, 5.5, 152, 3, 73, and 10 nM, respectively. We were surprised to find that maximal concentrations of risperidone and 9-OH-risperidone inhibited only 50% of the radiolabeling of h5-HT₇ receptors. These results indicate that risperidone and 9-OH risperidone may be producing 5-HT₇ receptor inactivation by different mechanisms than lisuride, bromocryptine, metergoline, and methiothepin. These results are not interpretable using the conventional model of G-protein-coupled receptor function. The complex seems capable of assuming a stable inactive conformation as a result of the interaction of certain antagonists. The rapid, potent inactivation of the receptor-G-protein complex by antagonists implies a constitutive, pre-existing complex between the h5-HT₇ receptor and a G-protein.

Received for publication September 16, 2008.

Accepted for publication November 7, 2008.

Address correspondence to: Dr. Milt Teitler, Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208. E-mail: teitlem{at}mail.amc.edu

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				N. Toohey, M. T. Klein, J. Knight, C. Smith, and M. Teitler Human 5-HT7 Receptor-Induced Inactivation of Forskolin-Stimulated Adenylate Cyclase by Risperidone, 9-OH-Risperidone and Other "Inactivating Antagonists" Mol. Pharmacol., September 1, 2009; 76(3): 552 - 559. [Abstract] [Full Text] [PDF]