Subtype-selective nicotinic receptor antagonists: potential as tobacco use cessation agents

• Published in: Bioorganic & medicinal chemistry letters 2004-04, Vol.14 (8), p.1863-1867
• Main Authors: Dwoskin, Linda P, Sumithran, Sangeetha P, Zhu, Jun, Deaciuc, A.Gabriela, Ayers, Joshua T, Crooks, Peter A
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biological Assay; Cholinergic system; Male; Medical sciences; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Nicotine - pharmacology; Nicotinic Antagonists - chemistry; Nicotinic Antagonists - pharmacology; Pharmacology. Drug treatments; Picolines - chemistry; Picolines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic - drug effects; Receptors, Nicotinic - metabolism; Smoking Cessation; Structure-Activity Relationship; Tobacco, tobacco smoking; Toxicology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2003.10.073

N-n-Alkylpicolinium and N,N′-alkyl-bis-picolinium analogues were assessed in nicotinic receptor (nAChR) assays. The most potent and subtype-selective analogue, N,N′-dodecyl-bis-picolinium bromide (bPiDDB), inhibited nAChRs mediating nicotine-evoked [ 3H]dopamine release (IC 50=5 nM; I max of 60%), and did not interact with α4β2* or α7* nAChRs. bPiDDB represents the current lead compound for development as a tobacco use cessation agent. N- n-Alkylpicolinium and N, N′-alkyl-bis-picolinium analogues were assessed in nicotinic receptor (nAChR) assays. The most potent and subtype-selective analogue, N, N′-dodecyl-bis-picolinium bromide (bPiDDB), inhibited nAChRs mediating nicotine-evoked [ 3H]dopamine release (IC 50=5 nM; I max of 60%), and did not interact with α4β2* or a7* nAChRs.