Factors influencing agonist potency and selectivity for the opioid delta receptor are revealed in structure-activity relationship studies of the 4-[(N-substituted-4-piperidinyl) arylamino]-N,N-diethylbenzamides

A study of the effect of transposition of the internal nitrogen atom for th e adjacent benzylic carbon atom in delta -selective agonists such as BW373U 86 (1) and SNC-80 (2) has been undertaken. It was shown that high-affinity, fully efficacious, and delta opioid receptor-selective compounds can be ob tained from this transposition. In addition to the N,N-diethylamido group n eeded as the delta address, the structural features identified to promote d elta receptor affinity in the set of compounds studied included a cis relat ive stereochemistry between the 3- and 4-substituents in the piperidine rin g, a trans-crotyl or allyl substituent on the basic nitrogen, the lack of a 2-methyl group in the piperidine ring, and either no substitution or hydro xyl substitution in the aryl ring not substituted with the N,N-diethylamido group. Structural features found to be important for mu affinity include h ydroxyl substitution in the aryl ring, the presence of a 2-methyl group in a cis relative relationship to the 4-amino group as well as N-substituents such as cyclopropylmethyl. It was also determined that mu receptor affinity could be increased while maintaining delta receptor affinity, especially w hen hydroxyl-substituted compounds are considered. Additionally, it was dis covered that the somewhat lower mu/delta selectivities observed for the pip eridine compounds relative to the piperazine-based ligands appear to arise as a consequence of the carbon-nitrogen transposition which imparts an over all lower delta and higher mu affinity to the piperidine-based ligands. Thi s higher affinity for the mu receptor, apparently intrinsic to the piperidi ne-based compounds, suggests that ligands of this class will more easily be converted to mu/delta combination agonists compared to the piperazine liga nds such as 1. This is particularly important since analogues of 1, which s how both mu- and delta -type activity, are now recognized as important for their strong analgesia and cross-canceling of many of the side effects foun d in agonists operating exclusively from either the delta or mu opioid rece ptor.