The Selective 5-HT<INF>1B</INF> Receptor Inverse Agonist 1‘-Methyl-5-[[2‘-methyl-4‘- (5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydro- spiro[furo[2,3-f]indole-3,4‘-piperidine] (SB-224289) Potently Blocks Terminal 5-HT Autoreceptor Function Both in Vitro and in Vivo

5-HT<INF>1</INF> receptors are members of the G-protein-coupled receptor superfamily and are negatively linked to adenylyl cyclase activity. The human 5-HT<INF>1B</INF> and 5-HT<INF>1D</INF> receptors (previously known as 5-HT<INF>1D</INF><INF>β</INF> and 5-HT<INF>1D</INF><INF>α</INF>, respectively), although encoded by two distinct genes, are structurally very similar. Pharmacologically, these two receptors have been differentiated using nonselective chemical tools such as ketanserin and ritanserin, but the absence of truly selective agents has meant that the precise function of the 5-HT<INF>1B</INF> and 5-HT<INF>1D</INF> receptors has not been defined. In this paper we describe how, using computational chemistry models as a guide, the nonselective 5-HT<INF>1B</INF>/5-HT<INF>1D</INF> receptor antagonist <BO>4</BO> was structurally modified to produce the selective 5-HT<INF>1B</INF> receptor inverse agonist <BO>5</BO>, 1‘-methyl-5-[[2‘-methyl-4‘-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4‘-piperidine] (SB-224289). This compound is a potent antagonist of terminal 5-HT autoreceptor function both in vitro and in vivo.