Probes for Narcotic Receptor Mediated Phenomena. 26. − Synthesis and Biological Evaluation of Diarylmethylpiperazines and Diarylmethylpiperidines as Novel, Nonpeptidic δ Opioid Receptor Ligands

• Published in: Journal of medicinal chemistry 1999-12, Vol.42 (26), p.5455-5463
• Main Authors: Zhang, Xiaoyan, Rice, Kenner C, Calderon, Silvia N, Kayakiri, Hiroshi, Smith, Larren, Coop, Andrew, Jacobson, Arthur E, Rothman, Richard B, Davis, Peg, Dersch, Christina M, Porreca, Frank
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Guinea Pigs; In Vitro Techniques; Ligands; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Medical sciences; Mice; Mice, Inbred ICR; Molecular Probes; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - metabolism; Piperazines - pharmacology; Radioligand Assay; Rats; Receptors, Opioid, delta - drug effects; Receptors, Opioid, delta - metabolism; Receptors, Opioid, delta - physiology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9903895

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 N 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.