title: Relationships between chemical structure and inhibition of choline acetyltransferase by 2-(alpha-naphthoyl)ethyltrimethylammonium and related compounds.
abstract: A choline acetyltransferase (ChA) inhibitor with an optimum combination of properties of potency, stability and membrane permeability is required to study several functional aspects of acetylcholine in nervous and non-nervous tissues. Therefore, 2-(alpha-naphthoyl)ethyltrimethylammonium iodide (alpha-NETA), 2-(beta-naphthoyl)ethyltrimethylammonium iodide (beta-NETA), 2-(9'-anthroyl)ethyltrimethylammonium iodide (9'-AETA) and their corresponding tertiary dimethylamine hydrochloride analogs (alpha-NEDA, beta-NEDA, 9'-AEDA) were synthesized and tested for their ChA inhibitory activities. The quaternary ammonium compounds were more potent inhibitors (150 in microM: alpha-NETA, 9; beta-NETA, 76; 9'-AETA, 32) than the corresponding tertiary compounds (150 in microM: alpha-NEDA, 63; beta-NEDA, 1400; 9'-AEDA, 77). The alpha-naphthyl moiety was preferable to the beta-naphthyl- or 9'-anthryl moieties for alignment with the enzyme for inhibition. alpha-NETA and alpha-NEDA exhibited adequate ChA inhibitory potencies for further pharmacological studies and localization of membrane bound ChA. They exhibited fluorescent characteristics of the alpha-naphthyl moiety. Their ChA inhibition was not reversible by dialysis. They were considerably more potent for inhibiting ChA than cholinesterases and carnitine acetyltransferase.
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
authors.forename: B V
authors.initials: BV
authors.lastname: Sastry
authors.forename: N
authors.initials: N
authors.lastname: Jaiswal
authors.forename: V
authors.initials: V
authors.lastname: Janson
authors.forename: P S
authors.initials: PS
authors.lastname: Day
authors.forename: R J
authors.initials: RJ
authors.lastname: Naukam
mesh_terms: D000109:Acetylcholine / Q000031:analogs & derivatives*; D002332:Carnitine O-Acetyltransferase / Q000037:antagonists & inhibitors; D002795:Choline O-Acetyltransferase / Q000037:antagonists & inhibitors*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D006801:Humans; D009281:Naphthalenes / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D009281:Naphthalenes; D000644:Quaternary Ammonium Compounds; C055734:2-naphthoylethyltrimethylammonium; D002795:Choline O-Acetyltransferase; D002332:Carnitine O-Acetyltransferase; D000109:Acetylcholine