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

We recently reported (+)-4-[(αR)-α-{(2S,5R)-4-allyl-2,5- dimethyl-1-piperazinyl}-3-methoxybenzyl]-N,N-diethylbenzamide (1b, SNC80) as a novel nonpeptidic δ receptor agonist and explored the structure-activity relationships (SAR) of a series of related derivatives. We have found that δ binding activities and selectivity showed little change when the 3-methoxy group in 1b was removed or replaced by the other substituents, whereas the N,N-diethylbenzamide group is important for interaction with the δ receptor. Extensive modification of the piperazine nucleus led to the synthesis of a new series of N,N-diethyl(α- piperazinylbenzyl)benzamides (2, 3a-e), N,N-diethyl(α- 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 δ receptor with K(i) values in the low nanomolar range. On the other hand, the binding affinities of these compounds for the μ and κ receptors were negligible, indicating excellent δ opioid receptor subtype selectivity. The two nitrogen atoms on the piperazine nucleus showed different SAR in the interaction of this series of compounds at the δ receptor. Nitrogen N⁴ appears to be an important structural element and is essential for electrostatic interaction, while N¹ seems to be unnecessary for recognition at the δ receptor.