Hybridized and isosteric analogues of N-1-acetyl-N-4-dimethy-piperazinium iodide (ADMP) and N-1-phenyl-N-4-dimethy-piperazinium iodide (DMPP) with central nicotinic action

A series of piperazine derivatives, obtained by hybridization of N-1-acetyl -N-4-dimethyl-piperazinium iodide (1, ADMP) and N-1-phenyl-N-4-dimethyl-pip erazinium iodide (3, DMPP) or of the corresponding tertiary bases (2, 4) wi th arecoline (5) and arecolone (6) or by isosteric substitution of the phen yl ring of DMPP, has been synthesized. Hybridization afforded compounds tha t, both as tertiary bases and as iodomethylates, have no affinity for the n icotinic receptor. On the contrary, isosteric substitution gave compounds t hat maintain affinity for the receptor; among them, two tertiary bases (37, 38), show affinity in the nanomolar range for the nicotinic receptor. The pharmacological profile of these isomeric compounds is quite interesting as they present differences in their peripheral and central effects, suggesti ng that they interact with different subtypes of the nicotinic receptor. (C ) 1999 Elsevier Science Ltd. All rights reserved.