Possible pharmacological and theoretical implications of X-ray structure of the tricyclic antidepressant imipramine

Abstract

IMIPRAMINE was first shown¹ in 1958 to be effective in the treatment of endogenous depression. It is one of the most widely prescribed members of the tricyclic antidepressant group of compounds which have been chosen for the treatment of the average depressed patient². It is perhaps snuprising that not a single member of this important group of psychotropic drugs has been investigated by X-ray analysis. There is now considerable evidence that a functional abnormality of one or more of the biogenic amine systems of the brain is involved in the aetiology of the depressive or affective disorders³. Amines which have been investigated most thoroughly in this respect are noradrenaline⁴ and 5-hydroxy-tryptamine⁵ (5-HT). The synaptic action of these putative neurotransmitters is thought to be terminated largely by an active uptake back into the presynaptic nerve ending, and the rat brain is known to possess separate neuronal uptake systems for noradrenaline⁶ and 5-HT⁷. The most striking neurochemical effect of tricyclic antidepressants is their potency in inhibiting these transport processes⁸, and indeed it has been suggested that this effect may be responsible for their clinical ameliorative action⁴. Structure-activity relationships for various imipramine analogues as inhibitors of noradrenaline⁹ and 5-HT^10,11 uptake have been reported and recently a possible molecular mechanism for this inhibitory effect has been proposed¹². In an attempt, therefore, to gain some insight into the conformational requirements for a compound to be a potent inhibitor of noradrenaline and 5-HT uptake, we are investigating the X-ray structures of a number of tricyclic antidepressants¹³; that of imipramine is reported here.