New diarylmethylpiperazines as potent and selective nonpeptidic delta opioid receptor agonists with increased in vitro metabolic stability

Nonpeptide delta opioid agonists are analgesics with a potentially improved side-effect and abuse liability profile, compared to classical opioids. An drews analysis of the NIH nonpeptide lead SNC-80 suggested the removal of s ubstituents not predicted to contribute to binding. This approach led to a simplified lead, N,N-diethyl-4-[phenyl( 1-piperazinyl)methyl]benzamide (1), which retained potent binding affinity and selectivity to the human delta receptor (IC50 = 11 nM, mu/delta = 740, kappa/delta > 900) and potency as a full agonist (EC50 = 36 nM) but had a markedly reduced molecular weight, o nly one chiral center, and increased in vitro metabolic stability. From thi s lead, the key pharmacophore groups for delta receptor affinity and activa tion were more clearly defined by SAR and mutagenesis studies. Further stru ctural modifications on the basis of 1 confirmed the importance of the N,N- diethylbenzamide group and the piperazine lower basic nitrogen for delta bi nding, in agreement with mutagenesis data. A number of piperazine N-alkyl s ubstituents were tolerated. In contrast, modifications of the phenyl group led to the discovery of a series of diarylmethylpiperazines exemplified by N,N-diethyl-4-[1-piperazinyl(8-quinolinyl)- methyl]benzamide (56) which had an improved in vitro binding profile (IC50 = 0.5 nM, mu/delta = 1239, EC50 = 3.6 nM) and increased in vitro metabolic stability compared to SNC-80.