title: Functional inhibition of intestinal and uterine muscles by non-permeant triphenylethylene derivatives.
abstract: We have previously shown that the triphenylethylene antiestrogen tamoxifen reversibly inhibited spontaneous contractile activity in isolated duodenal muscle. Now, we have synthesized different quaternary ammonium salts of tamoxifen by changing the substituents on the nitrogen of the alkylaminoethoxy side-chain, to obtain plasma membrane impermeable compounds. Synthesized molecules were N-desmethyl-tamoxifen-hydrochloride, ethylbromide-tamoxifen and butylbromide-tamoxifen, which differed in the size of their ionic side-chain. All compounds rapidly and reversibly inhibited spontaneous and CaCl(2)-induced contractions in mouse duodenum and uterus. Dose-response analyses revealed a structure-activity relationship where the larger the side-chain the higher the inhibitory potency. Fourier analyses on triphenylethylene-relaxed duodenal tissues showed that harmonic components of contractile activity were readily recovered upon exposure to the L-type calcium channel agonist 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-pyridine-3-carboxilic acid methyl ester (BAY-K644). Likewise, BAY-K644 completely reversed triphenylethylene-induced effects on uterine tonic tension. Our experiments suggest that impermeant tamoxifen derivatives relax visceral smooth muscle through a membrane-mediated non-genomic mechanism that involves inhibition of L-type calcium channels.
authors.affiliation: Laboratorio de Fisiología Animal, Departamento de Biología Animal, Universidad de La Laguna, 38206 Tenerife, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Marrero-Alonso
authors.forename: Benito
authors.initials: B
authors.lastname: García Marrero
authors.forename: Tomás
authors.initials: T
authors.lastname: Gómez
authors.forename: Mario
authors.initials: M
authors.lastname: Díaz
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002122:Calcium Chloride / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004386:Duodenum / Q000187:drug effects* / Q000502:physiology; D004965:Estrogen Antagonists / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000737:chemistry / Q000494:pharmacology; D014320:Triphenylmethyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D014599:Uterus / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D002120:Calcium Channel Agonists; D004965:Estrogen Antagonists; D026902:Potassium Channel Blockers; D014320:Triphenylmethyl Compounds; D014665:Vasodilator Agents; D013629:Tamoxifen; D011189:Potassium Chloride; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C046945:triphenylmethane; D002122:Calcium Chloride; D000109:Acetylcholine