Dopamine receptor blockade by imidoline and its proposed active conformation

Imidoline, 1-[2-(N,N-dimethylamino)ethyl]-3-m-chlorophenyl-2-imidazolidinone, has been found to be as potent as chlorpromazine in increasing striatal DOPA accumulation and prolactin secretion in vivo. In contrast, imidoline exhibited only weak inhibitory activity towards dopamine-sensitive adenylate cyclase and 3H-spiroperidol binding to striatal membranes in vitro. These neuroleptic effects in vivo are probably caused by blockade of dopamine receptors since imidoline did not deplete the striatum of dopamine. Imidoline is of interest because its structure is distinct from those of other neuroleptics. A proposed active conformation involves intramolecular hydrogen bonding between the protonated dimethylamino group and the oxygen of the imidazolidinone ring. The spatial relationship between the amine nitrogen and phenyl ring in this conformation allows proper fit of imidoline with key dimensions described for the dopamine receptor.