Stereoselective effects of the potentially neuroleptic rigid spiro amines

Abstract

WE HAVE reported the synthesis and pharmacological effects of a novel series of tetracyclic spiro compounds structurally related to the tricyclic antidepressants¹. In contrast to the common tricyclic antidepressants, the terminal amino group of the spiro compounds has restricted mobility. As expected, some of these compounds have antidepressant properties in model systems, for example they are potent blockers of the neuronal uptake of noradrenaline in the central nervous system. But the compounds containing a chlorine atom in the tricyclic moiety have a neuroleptic profile in animal tests. 3-Chloro-10,11-dihydro-N,N-dimethylspiro-[5H-dibenzo [a,d]cycloheptene-5,1′-cyclohex-2′-ene]-4′-amine, structure (I), is particularly interesting in this respect. The cyclohexene ring in this structure is located perpendicularly to the tricyclic ring system and as a consequence the amino group can occupy a position either cis or trans to the chlorine-containing part of the tricyclic ring system. Furthermore, the cis and trans isomers can be resolved into enantiomers as the molecule contains two chiral centres (marked with asterisks in structure (I)). Several studies have yielded results to favour the view that neuroleptic drugs act as dopamine (DA) antagonists in the brain^2,3 and that the DA receptor blockade is rather well correlated with their antipsychotic efficiency^4–6. The neuroleptics seem to block chiefly postsynaptic DA receptors, particularly in striatal⁷ and mesolimbic⁸ DA areas of the brain. The rigid nature of the isomeric tetracyclic spiro amines of structure (I), and the possibility of stereospecific pharmacological effects make these compounds interesting tools for an investigation of the structural requirements for DA receptor blockade and for studies on DA receptor topology.