Design and stereoselective synthesis of conformationally constrained analogues of Zimeldine

Abstract

Most of the commonly used antidepressant drug (e. g. imipramine and amitriptyline) have cardiovascular side effects (orthostatic hypotension, tachycardia, arrhythmia) due to the action of these drugs at cholinergic and adrenergic sites (Ankier, 1986). The goal of this research program is to design and sythesize very selective inhibitors for the uptake of either, but not both, norepinephrine (NE) or serotonin (5HT). Examining the relation between the conformation of these molecules and their selectivity for inhibition of the uptake of NE or 5HT could provide an understanding of the molecular mechanisms involved. Such information could lead to even safer antidepressant drugs with diminished cardiovascular side effects. Furthermore, drugs that are selective for inhibition of the uptake of 5HT (e.g. fluoxetine) show promise as aspects for obesity control (Grunewald et al., 1986a). In order to find new drugs with enhanced selectivity for the uptake of 5HT which could be useful as antidepressants requires an understanding of the structural features of these drugs that results in their selectivity for the 5HT uptake carrier. As part of a search for the explanation of the dramatic pharmacological difference between (Z)-Zimeldine (1, a selective inhibitor of the reuptake of serotonin) and (E)-Zimeldine (2, a selective inhibitor of norepinephrine) in presynaptic nerve endings (Hoberg et al., 1981), we sought a convenient synthesis of conformationally defined analogues of 1 and 2 in the quinoline and naphthalene skeleton. We wondered if subtle changes in low energy conformations of the