THE SELECTIVE 5-HT1B RECEPTOR INVERSE AGONIST TETRAHYDROSPIRO[FURO[2,3-F]INDOLE-3,4'-PIPERIDINE] (SB-224289) POTENTLY BLOCKS TERMINAL 5-HT AUTORECEPTOR FUNCTION BOTH IN-VITRO AND IN-VIVO

5-HT1 receptors are members of the G-protein-coupled receptor superfam ily and are negatively Linked to adenylyl cyclase activity. The human 5-HT1B and 5-HT1D receptors (previously known as 5-HT1D beta and 5-HT1 D alpha, respectively), although encoded by two distinct genes, are st ructurally very similar. Pharmacologically, these two receptors have b een differentiated using nonselective chemical tools such as ketanseri n and ritanserin, but the absence of truly selective agents has meant that the precise function of the 5-HT1B and 5-HT1D receptors has not b een defined. In this paper we describe how, using computational chemis try models as a guide, the nonselective 5-HT1B/5-HT1D receptor antagon ist 4 was structurally modified to produce the selective 5-HT1B recept or inverse agonist 5, tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidin e] (SB-224289). This compound is a potent antagonist of terminal 5-HT autoreceptor function both in vitro and in vivo.