FUNCTIONAL-CHARACTERIZATION OF THE HUMAN CLONED 5-HT7 RECEPTOR (LONG FORM) - ANTAGONIST PROFILE OF SB-258719

1 The functional profile of the long form of the human cloned 5-HT7 re ceptor (designated h5-HT7(a)) was investigated using a number of 5-HT receptor agonists and antagonists and compared with its binding profil e. Receptor function was measured using adenylyl cyclase activity in w ashed membranes from HEK293 cells stably expressing the recombinant h5 -HT7(a) receptor. 2 The receptor binding profile, determined by compet ition with [H-3]-5-CT, was consistent with that previously reported fo r the h5-HT7(a) receptor. The selective 5-HT7 receptor antagonist SE-2 58719 [1-methyl-3-(4-methylpiperidin-1-yl)propyl]benzene sulfonamide) displayed high affinity (pK(i) 7.5) for the receptor. 3 In the adenyly l cyclase functional assay, 5-CT and 8-OH-DPAT were both full agonists compared to 5-HT and the rank order of potency for agonists (5-CT > 5 -HT > 8-OH-DPAT) was the same in functional and binding studies. 4 Ris peridone, methiothepin, mesulergine, clozapine, olanzapine, ketanserin and SE-258719 antagonised surmountably 5-CT-stimulated adenylyl cycla se activity. Schild analysis of the antagonism by SB-258719 gave a pA( 2) of 7.2 +/- 0.2 and slope not significantly different from 1, consis tent with competitive antagonism. 5 The same antagonists also inhibite d basal adenylyl cyclase activity with a rank order of potency in agre ement with those for antagonist potency and binding affinity. Both SB- 258719 and mesulergine displayed apparent partial inverse agonist prof iles compared to the other antagonists tested. These inhibitory effect s of antagonists appear to be 5-HT7 receptor-mediated and to reflect i nverse agonism. 6 It is concluded that in this expression system, the h5-HT7(a) receptor shows the expected binding and functional profile a nd displays constitutive activity, revealing inverse agonist activity for a range of antagonists.