title: Aporphine metho salts as neuronal nicotinic acetylcholine receptor blockers.
abstract: (S)-Aporphine metho salts with the 1,2,9,10 oxygenation pattern displaced radioligands from recombinant human alpha7 and alpha4beta2 neuronal nicotinic acetylcholine receptors (nAChR) at low micromolar concentrations. The affinity of the nonphenolic glaucine methiodide (4) (vs [(3)H]cytisine) was the lowest at alpha4beta2 nAChR (K(i)=10 microM), and predicentrine methiodide (2) and xanthoplanine iodide (3), with free hydroxyl groups at C-2 or C-9, respectively, had the highest affinity at these receptors (K(i) approximately 1 microM), while the affinity of the diphenolic boldine methiodide (1) was intermediate between these values. At homomeric alpha7 nAChR, xanthoplanine had the highest affinity (K(i)=10 microM) vs [(125)I]alpha-bungarotoxin while the other three compounds displaced the radioligand with K(i) values between 15 and 21 microM. At 100 microM, all four compounds inhibited the responses of these receptors to EC(50) concentrations of ACh. The effects of xanthoplanine iodide (3) were studied in more detail. Xanthoplanine fully inhibited the EC(50) ACh responses of both alpha7 and alpha4beta2 nACh receptors with estimated IC(50) values of 9+/-3 microM (alpha7) and 5+/-0.8 microM (alpha4beta2).
authors: Department of Chemistry, Faculty of Sciences, University of Chile, Casilla 653, Santiago, Chile.
authors: Patricio
authors: P
authors: Iturriaga-Vásquez
authors: Edwin G
authors: EG
authors: Pérez
authors: E Yvonne
authors: EY
authors: Slater
authors: Isabel
authors: I
authors: Bermúdez
authors: Bruce K
authors: BK
authors: Cassels
mesh_terms: D000818:Animals; D001060:Aporphines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D009474:Neurons / Q000187:drug effects*; D018733:Nicotinic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011978:Receptors, Nicotinic / Q000187:drug effects*; D014162:Transfection; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D001060:Aporphines; C579167:Chrna7 protein, human; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; C011686:boldine