NOVEL 5-HT3 ANTAGONISTS - DOL-3-YLSPIRO(AZABICYCLOALKANE-3,5'(4'H)-OXAZOLES)

The synthesis and biochemical evaluation of a series of spirofused ind ole oxazoline 5-HT3 antagonists is described in which the oxazoline ri ng acts as a bioisosteric replacement for esters and amides. The effec t of substitution about the indole ring has shown the steric limitatio ns of the aromatic binding site. Incorporation of a variety of azabicy clic systems within the rigid spirofused framework has allowed the def inition of a binding model which incorporates a number of known antago nists and agonists. In this model steric constraints limit substitutio n around the indole ring although there is some bulk tolerance at the 1- and 2-positions. The importance of constraining the basic nitrogen within an azabicyclic system is underlined by comparison with the mono cyclic piperidine. The highest affinity was observed for those compoun ds in which the basic nitrogen occupies a bridgehead position, the mos t potent analogue in this group being the azabicyclic [3.3.1] system ( pIC50 = 8.95), suggesting lipophilic interactions may play a role in i ncreasing affinity. A suggested model for agonist binding is included in which the basic nitrogens are superimposed and the 5-hydroxyl group of 5-HT is superimposed on the H-bond-accepting atom of the heterocyc lic linking group.