Probes for narcotic receptor mediated phenomena. 26. Synthesis and biological evaluation of diarylmethylpiperazines and diarylmethylpiperidines as novel, nonpeptidic delta opioid receptor ligands

We recently reported (+)-4-[(alpha R)-alpha-{(2S,5R)-4-allyl-2,5-dimethyl-1 -piperazinyl}-3-methoxybenzyl]-N,N-diethylbenzamide (1b, SNC80) as a novel nonpeptidic delta receptor agonist and explored the structure-activity rela tionships (SAR) of a series of related derivatives. We have found that delt a binding activities and selectivity showed little change when the S-methox y group in Ib was removed or replaced by the other substituents, whereas th e N,N-diethylbenzamide group is important for interaction with the delta re ceptor. Extensive modification of the piperazine nucleus led to the synthes is of a new series of N,N-diethyl(alpha-piperazinylbenzyl)benzamides (2, 3 a-e), N,N- diethyl(alpha-piperidinyl or piperidinylidenebenzyl)benzamides ( 4a, 5a-c, 6a-b), and related derivatives (4b, 7a-c). Several compounds (2, 3a, 3e, 6a) strongly bound to the delta receptor with K-i values in the low nanomolar range. On the other hand, the binding affinities of these compou nds for the mu and kappa receptors were negligible, indicating excellent de lta opioid receptor subtype selectivity. The two nitrogen atoms on the pipe razine nucleus showed different SAR in the interaction of this series of co mpounds at the delta receptor. Nitrogen N-4 appears to be an important stru ctural element and is essential for electrostatic interaction, while N-1 se ems to be unnecessary for recognition at the delta receptor.