PT  - JOURNAL ARTICLE
AU  - Knight, Jessica A.
AU  - Smith, Carol
AU  - Toohey, Nicole
AU  - Klein, Michael T.
AU  - Teitler, Milt
TI  - Pharmacological Analysis of the Novel, Rapid, and Potent Inactivation of the Human 5-Hydroxytryptamine<sub>7</sub> Receptor by Risperidone, 9-OH-Risperidone, and Other Inactivating Antagonists
AID  - 10.1124/mol.108.052084
DP  - 2009 Feb 01
TA  - Molecular Pharmacology
PG  - 374--380
VI  - 75
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/75/2/374.short
4100  - http://molpharm.aspetjournals.org/content/75/2/374.full
SO  - Mol Pharmacol2009 Feb 01; 75
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics