New Diarylmethylpiperazines as Potent and Selective Nonpeptidic δ Opioid Receptor Agonists with Increased In Vitro Metabolic Stability

• Published in: Journal of medicinal chemistry 2000-10, Vol.43 (21), p.3878-3894
• Main Authors: Plobeck, Niklas, Delorme, Daniel, Wei, Zhong-Yong, Yang, Hua, Zhou, Fei, Schwarz, Peter, Gawell, Lars, Gagnon, Hélène, Pelcman, Benjamin, Schmidt, Ralf, Yue, Shi Yi, Walpole, Christopher, Brown, William, Zhou, Edward, Labarre, Maryse, Payza, Kemal, St-Onge, Stephane, Kamassah, Augustus, Morin, Pierre-Emmanuel, Projean, Denis, Ducharme, Julie, Roberts, Edward
• Format: Article
• Language: English
• Subjects: Animals; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - metabolism; Biological and medical sciences; Biological Availability; Cell Line; Chromatography, High Pressure Liquid; Humans; In Vitro Techniques; Mass Spectrometry; Medical sciences; Microsomes, Liver - metabolism; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - metabolism; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - metabolism; Radioligand Assay; Rats; Receptors, Opioid, delta - agonists; Receptors, Opioid, delta - metabolism; Receptors, Opioid, kappa - metabolism; Receptors, Opioid, mu - metabolism; Stereoisomerism; Structure-Activity Relationship; Thermodynamics; Transfection
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000228x

Nonpeptide δ opioid agonists are analgesics with a potentially improved side-effect and abuse liability profile, compared to classical opioids. Andrews analysis of the NIH nonpeptide lead SNC-80 suggested the removal of substituents 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 δ receptor (IC50 = 11 nM, μ/δ = 740, κ/δ > 900) and potency as a full agonist (EC50 = 36 nM) but had a markedly reduced molecular weight, only one chiral center, and increased in vitro metabolic stability. From this lead, the key pharmacophore groups for δ receptor affinity and activation were more clearly defined by SAR and mutagenesis studies. Further structural modifications on the basis of 1 confirmed the importance of the N,N-diethylbenzamide group and the piperazine lower basic nitrogen for δ binding, in agreement with mutagenesis data. A number of piperazine N-alkyl substituents 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, μ/δ = 1239, EC50 = 3.6 nM) and increased in vitro metabolic stability compared to SNC-80.