ELECTROPHYSIOLOGICAL, BIOCHEMICAL, NEUROHORMONAL AND BEHAVIORAL-STUDIES WITH WAY-100635, A POTENT, SELECTIVE AND SILENT 5-HT1A RECEPTOR ANTAGONIST

Although considerable progress has been made in characterising the 5-H T1A receptor using agonists, partial agonists or nonselective antagoni sts, further studies of 5-HT1A receptor function have been kindered by the lack of highly selective antagonists. The term 'silent' antagonis t has been used for such compounds in order to distinguish them unequi vocally from several 5-HT1A receptor partial agonists which were initi ally designated 'antagonists'. In this report we provide a comprehensi ve review of the biochemical, pharmacological and behavioural properti es of the first potent, selective and silent 5-HT1A receptor antagonis t, WAY-100635 zinyl]ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide trihy drochloride). WAY-100635 had an IC50 (displacement of specific [H-3]8- OH-DPAT binding to 5-HT1A receptors in the rat hippocampus) of 1.35 nM and was >100-fold selective for the 5-HT1A site relative to a range o f other CNS receptors. [H-3]WAY-100635 was also characterised as the f irst 5-HT1A antagonist radioligand, displaying the same regional distr ibution of binding sites as [H-3]8-OH-DPAT in rat brain. As would be e xpected for the binding of an antagonist to a G-protein-coupled recept or, the B-max of [H-3]WAY-100635 specific binding was consistently 50- 60% greater than that of the agonist radioligand, [H-3]8-OH-DPAT. Mn2, but not guanine nucleotides, inhibited [H-3]WAY-100635-specific bind ing. [H-3]WAY-100635 was also shown to bind selectively to brain 5-HT1 A receptors in vivo, following intravenous administration to mice. In vitro electrophysiological studies demonstrated that WAY-100635 had no 5-HT1A receptor agonist actions, but dose-dependently blocked the eff ects of agonists at both the postsynaptic 5-HT1A receptor in the CA1 r egion of the hippocampus, and the somatodendritic 5-HT1A receptor loca ted on dorsal raphe 5-HT neurones. In vivo, WAY-100635 also dose-depen dently blocked the ability of 8-OH-DPAT to inhibit the firing of dorsa l raphe 5-HT neurones, and to induce the '5-HT syndrome', hypothermia, hyperphagia and to elevate plasma ACTH levels. In the mouse light/dar k box anxiety model, WAY-100635 induced anxiolytic-like effects. WAY-1 00635 had no intrinsic effect on cognition in the delayed-matching-to- position model of short-term memory in the rat, but reversed the disru ptive effects of 8-OH-DPAT on motor/motivational performance. These da ta clearly demonstrate that WAY-100635 is the first potent, selective and silent 5-HT1A receptor antagonist. Furthermore, [3H]WAY-100635 is the first antagonist radioligand to become available for 5-HT1A recept or binding studies both in vitro and in vivo. The positive effects of WAY-100635 in an anxiety model also indicate that a postsynaptic 5-HT1 A receptor antagonist action may contribute to the anxiolytic properti es of 5-HT1A receptor partial agonists.