Synthesis and Pharmacological Evaluation of Novel Octahydro-1H-pyrido[1,2-a]pyrazine as μ-Opioid Receptor Antagonists

• Published in: Journal of medicinal chemistry 2006-12, Vol.49 (25), p.7290-7306
• Main Authors: Le Bourdonnec, Bertrand, Goodman, Allan J, Graczyk, Thomas M, Belanger, Serge, Seida, Pamela R, DeHaven, Robert N, Dolle, Roland E
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; CHO Cells; Cricetinae; Cricetulus; Crystallography, X-Ray; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Humans; Ligands; Medical sciences; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Pyrazines - chemical synthesis; Pyrazines - chemistry; Pyrazines - pharmacology; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Radioligand Assay; Receptors, Opioid, delta - antagonists & inhibitors; Receptors, Opioid, kappa - antagonists & inhibitors; Receptors, Opioid, mu - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0604878

To better understand structural requirements for a μ ligand of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class to interact with the μ opioid receptor, we have described in the previous article (Le Bourdonnec, B. et al. J. Med. Chem. 2006, 25, 7278−7289) new, constrained analogues of the N-phenethyl derivative 3. One of the active constrained analogues, compound 4, exhibited subnanomolar μ-opioid receptor affinity (K i = 0.62 nM) and potent μ-opioid antagonist activity (IC50 = 0.54 nM). On the basis of structure 4, a new series of μ-opioid receptor antagonists were designed. In these compounds the octahydroquinolizine template of 4 was replaced by an octahydro-1H-pyrido[1,2-a]pyrazine scaffold. The new derivatives were tested for their binding affinities and in vitro functional activity against the cloned human μ-, δ-, and κ-opioid receptors. From this study, we identified compound 36, which displays high affinity toward the μ-opioid receptor (K i = 0.47 nM), potent μ in vitro antagonist activity (IC50 = 1.8 nM) and improved binding selectivity profile μ/κ and μ/δ, when compared to 4.