Synthesis of new opioid derivatives with a propellane skeleton and their pharmacology. Part 2: Propellane derivatives with an amide side chain

• Published in: Bioorganic & medicinal chemistry letters 2012-04, Vol.22 (8), p.2775-2779
• Main Authors: Nagase, Hiroshi, Akiyama, Junko, Nakajima, Ryo, Hirayama, Shigeto, Nemoto, Toru, Gouda, Hiroaki, Hirono, Shuichi, Fujii, Hideaki
• Format: Article
• Language: English
• Subjects: agonists; Amides - chemistry; Amides - pharmacology; Analgesics, Opioid - chemical synthesis; Analgesics, Opioid - chemistry; Analgesics, Opioid - pharmacology; Biological and medical sciences; Bridged-Ring Compounds - chemistry; Bridged-Ring Compounds - pharmacology; chemical derivatives; Lone electron pair; Medical sciences; Models, Molecular; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Opioid; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; pharmacology; Pharmacology. Drug treatments; Propellane derivative; Protein Binding - drug effects; Receptors, Opioid, kappa - agonists; Shielding effect
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.02.082

We designed and synthesized propellane derivatives with a 6- or 7-amide side chain on the basis of the active conformation of the κ selective agonist nalfurafine. The 6-amides showed high affinities for the κ receptor, and one of the 6β-amides showed higher κ selectivity than nalfurafine. On the other hand, although the affinities of the 7-amides decreased compared to the 6-amides, some 7α-amides showed the highest selectivities for the κ receptor among the tested compounds. The affinities of 7β-isomers were extremely low, which was postulated to result from the shielding effect of the 7β-amide side chain against the lone electron pair on the 17-nitrogen. This is the first conformational information about the 7-amide side chain in propellane derivatives.