title: Effects of 1-cyclohexyl- and 1-cyclohexyl-N-propargyl-1,2,3,4-tetrahydroisoquinoline on dopaminergic spontaneous discharge in nigral neurons of rats.
abstract: 1,2,3,4-Tetrahydroisoquinoline (TIQ) and some of its derivatives, such as 1-benzyl-TIQ and 1-methyl-TIQ, are endogenously present in human brain and are thought to contribute to induction or prevention of Parkinson's disease. In the present study, we estimated the effects of the artificially synthesized TIQ derivatives 1-cyclohexyl-TIQ (1-cHex-TIQ) and 1-cyclohexyl-N-propargyl-TIQ (1-cHex-N-proTIQ) on spontaneous nigral dopaminergic discharge in rats. Low to middle doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced a transient and significant, but not relatively potent, increase in the firing rate, followed by a sustained decrease with higher doses. 1-cHex-TIQ increased the firing frequency at low and high doses. In contrast, 1-cHex-N-proTIQ had no effects on spontaneous firing. Although intraperitoneal pretreatment with 1-cHex-TIQ did not inhibit this MPTP-induced decrease in firing, pretreatment with 1-cHex-N-proTIQ significantly depressed this decreased firing in a dose-dependent and long-lasting manner. Selegiline, a monoamine oxidase type B inhibitor that is used as a therapeutic drug for Parkinson's disease, also significantly inhibited the decrease in dopaminergic spontaneous firing induced by MPTP, but the effect was transient. These results suggest that although the decrease in firing induced by 1-cHex-TIQ is clearly more potent compared to that induced by MPTP, its effect is eliminated by adding an N-propargyl functional group. The antagonizing effect of 1-cHex-N-proTIQ on MPTP-induced firing loss may be exerted by a different mechanism than that of selegiline.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Ohu University, 31-1 Tomitamachi, Koriyama, Fukushima 963-8611, Japan.
authors.forename: Momoko
authors.initials: M
authors.lastname: Abe
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Ohu University, 31-1 Tomitamachi, Koriyama, Fukushima 963-8611, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Munakata
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Ohu University, 31-1 Tomitamachi, Koriyama, Fukushima 963-8611, Japan. Electronic address: k-abe@pha.ohu-u.ac.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Abe
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Nihon Pharmaceutical University, 10281 Inamachi, Kita-adachigun, Saitama 362-0806, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Medicinal Chemistry, Showa Pharmaceutical University, 3-3165 Higashitamagawagakuen, Machida, Tokyo 194-0042, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Horiguchi
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Ohu University, 31-1 Tomitamachi, Koriyama, Fukushima 963-8611, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nojima
authors.affiliation: Department of Medicinal Pharmacology, Showa Pharmaceutical University, 3-3165 Higashitamagawagakuen, Machida, Tokyo 194-0042, Japan.
authors.forename: Kyoji
authors.initials: K
authors.lastname: Taguchi
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D004347:Drug Interactions; D008297:Male; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D013378:Substantia Nigra / Q000166:cytology*; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000494:pharmacology*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D015259:Dopamine Agents; D009498:Neurotoxins; D044005:Tetrahydroisoquinolines; D017392:Thiobarbituric Acid Reactive Substances; C014843:1,2,3,4-tetrahydroisoquinoline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine
keywords: 1,2,3,4-Tetrahydroisoquinoline; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Parkinson’s disease; Rat; Selegiline; Spontaneous discharge