title: Structure-activity studies with ring E analogues of methyllycaconitine on bovine adrenal alpha3beta4* nicotinic receptors.
abstract: The development of new agents that selectively interact with subtypes of neuronal nicotinic receptors (nAChRs) is of primary importance for the study of physiological processes and pathophysiological conditions involving these receptors. Our laboratory has evidence that simple ring E analogues of methyllycaconitine (MLA) act as antagonists to bovine adrenal alpha3beta4* nAChRs. The following studies were designed to characterize the concentration-response effects of several ring E analogues of MLA in order to assess structural requirements involved with their inhibitory activity on bovine adrenal alpha3beta4* nAChRs. Ring E analogues with various substitutions on the ring E nitrogen were tested for their ability to inhibit nicotinic stimulated adrenal catecholamine release and [3H]epibatidine binding to a bovine adrenal membrane preparation. Several N-alkyl derivatives inhibited secretion with IC50 values in the low micromolar range. The N-phenpropyl analogue was the most potent of the analogues tested (IC50, 11 microM) on adrenal secretion. Competition binding studies suggest a noncompetitive interaction of the analogues with bovine adrenal nAChRs. These studies identify several structural features of ring E analogues of MLA which significantly affect their inhibitory activity on bovine adrenal alpha3beta4* nAChRs.
authors.affiliation: Division of Pharmacology, The Ohio State University, College of Pharmacy, 500 West 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Darrell L
authors.initials: DL
authors.lastname: Bryant
authors.forename: R Benjamin
authors.initials: RB
authors.lastname: Free
authors.forename: Sara M
authors.initials: SM
authors.lastname: Thomasy
authors.forename: David J
authors.initials: DJ
authors.lastname: Lapinsky
authors.forename: Khadiga A
authors.initials: KA
authors.lastname: Ismail
authors.forename: Susan B
authors.initials: SB
authors.lastname: McKay
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Bergmeier
authors.forename: Dennis B
authors.initials: DB
authors.lastname: McKay
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D000313:Adrenal Medulla / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D002395:Catecholamines / Q000378:metabolism*; D002417:Cattle; D019439:Chromaffin Cells / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
chemical_list: D002395:Catecholamines; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; C054634:methyllycaconitine; D000157:Aconitine