Factors Influencing Agonist Potency and Selectivity for the Opioid δ Receptor Are Revealed in Structure−Activity Relationship Studies of the 4-[(N-Substituted-4-piperidinyl)arylamino]-N,N-diethylbenzamides

• Published in: Journal of medicinal chemistry Vol. 44; no. 6; pp. 972 - 987
• Main Authors: Thomas, James B, Herault, Xavier M, Rothman, Richard B, Atkinson, Robert N, Burgess, Jason P, Mascarella, S. Wayne, Dersch, Christina M, Xu, Heng, Flippen-Anderson, Judith L, George, Clifford F, Carroll, F. Ivy
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 15-03-2001
• Subjects: Animals; Benzamides - chemistry; Benzamides - metabolism; Biological and medical sciences; Brain - metabolism; Crystallography, X-Ray; Guinea Pigs; In Vitro Techniques; Ligands; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Piperazines - chemistry; Piperazines - metabolism; Piperidines - chemistry; Piperidines - metabolism; Radioligand Assay; Rats; Receptors, Opioid, delta - metabolism; Receptors, Opioid, kappa - metabolism; Receptors, Opioid, mu - metabolism; Stereoisomerism; Structure-Activity Relationship; Agonist; Structure activity relation; Aminoamide; Nitrogen heterocycle; Piperidine derivatives; Phenols; Benzamide derivatives; Benzenic compound; Selectivity; δ Opioid receptor; Chemical synthesis; In vitro
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000427g

A study of the effect of transposition of the internal nitrogen atom for the adjacent benzylic carbon atom in δ-selective agonists such as BW373U86 (1) and SNC-80 (2) has been undertaken. It was shown that high-affinity, fully efficacious, and δ opioid receptor-selective compounds can be obtained from this transposition. In addition to the N,N-diethylamido group needed as the δ address, the structural features identified to promote δ receptor affinity in the set of compounds studied included a cis relative stereochemistry between the 3- and 4-substituents in the piperidine ring, 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 hydroxyl substitution in the aryl ring not substituted with the N,N-diethylamido group. Structural features found to be important for μ affinity include hydroxyl 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 μ receptor affinity could be increased while maintaining δ receptor affinity, especially when hydroxyl-substituted compounds are considered. Additionally, it was discovered that the somewhat lower μ/δ selectivities observed for the piperidine compounds relative to the piperazine-based ligands appear to arise as a consequence of the carbon−nitrogen transposition which imparts an overall lower δ and higher μ affinity to the piperidine-based ligands. This higher affinity for the μ receptor, apparently intrinsic to the piperidine-based compounds, suggests that ligands of this class will more easily be converted to μ/δ combination agonists compared to the piperazine ligands such as 1. This is particularly important since analogues of 1, which show both μ- and δ-type activity, are now recognized as important for their strong analgesia and cross-canceling of many of the side effects found in agonists operating exclusively from either the δ or μ opioid receptor.