Inhibition of the constitutive activity of human 5‐HT1A receptors by the inverse agonist, spiperone but not the neutral antagonist, WAY 100,635

At recombinant human 5-hydroxytryptamine (5-HT)5-HT1A receptors expressed in Chinese hamster ovary cells (CHO-5-HT1A), 5-carboxamidotryptamine (5-CT), acted as a full agonist (relative to 5-HT = 100%) for stimulation of receptor-mediated [35S]-GTP gamma S (guanylyl 5'-[gamma-thio]-tryphosphate) binding. In contrast, spiperone inhibited basal [35S]-GTP gamma S binding by 30.2% (IC50 = 55.5 nM) in CHO-5-HT1A membranes but not in control untransfected membranes. The antagonist, N-[2-[4-(2-methoxyphenyl) -1-piperazinyl]ethyl]-N-(2-pyridinyl)-cyclohexane-carboxamide (WAY 100,635), blocked both 5-CT-induced stimulation and spiperone-induced inhibition of [35S]-GTP gamma S binding without itself modifying [35S]-GTP gamma S binding. It is concluded that, in this heterologous expression system, 5-HT1A receptors display 'constitutive' activation of G-proteins and that spiperone displays inverse agonist activity whereas WAY 100,635 acts as a 'neutral' antagonist at this site.