title: Cartap hydrolysis relative to its action at the insect nicotinic channel.
abstract: The insecticide cartap is the bis(thiocarbamate) derivative of 2-(dimethylamino)propane-1,3-dithiol, which on oxidation forms the natural toxicant nereistoxin (NTX) [4-(dimethylamino)-1,2-dithiolane]. Both cartap and NTX are ion channel blockers of the nicotinic acetylcholine receptor (nAChR). Cartap was originally proposed to act only after metabolic conversion to NTX and later suggested to block directly without activation. The present study uses a new approach to differentiate these hypotheses, that is, pH effects on channel-blocking activity and hydrolysis rates. As controls, mecamylamine (the classic channel blocker) and NTX are stable and similar in channel-blocking potency ([(3)H]thienylcyclohexylpiperidine binding assay, honeybee nAChR) at pH 6.1-8.4. In contrast, cartap is >200-fold more effective at pH 7.4 than at pH 6.1, indicating that it undergoes hydrolytic activation. Cartap slowly hydrolyzes to cartap monothiol at pH 6.1 but quickly forms the dithiol and some NTX at pH 7.4. The relationship between potency and hydrolysis products at various pH ranges suggests that cartap dithiol is the most plausible blocking agent.
authors.affiliation: Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112, USA.
authors.forename: Seog-Jong
authors.initials: SJ
authors.lastname: Lee
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Caboni
authors.forename: Motohiro
authors.initials: M
authors.lastname: Tomizawa
authors.forename: John E
authors.initials: JE
authors.lastname: Casida
mesh_terms: D000818:Animals; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007313:Insecta / Q000737:chemistry*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry; D013859:Thiocarbamates / Q000737:chemistry* / Q000494:pharmacology*; D014050:Toluene / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D011978:Receptors, Nicotinic; D013438:Sulfhydryl Compounds; D013859:Thiocarbamates; D014050:Toluene; C004848:dithiol; C032761:carbamothioic acid, S,S'-(2-(dimethylamino)-1,3-propanediyl) ester