title: JL13 has clozapine-like actions on thermoregulatory cutaneous blood flow in rats: Involvement of serotonin 5-HT1A and 5-HT2A receptor mechanisms.
abstract: Clozapine is an effective atypical antipsychotic agent, with serious side effects. JL13 [5-(4-methylpiperazin-1-yl)-8-chloropyrido[2,3-b][1,5]benzoxazepine] is a potential new atypical antipsychotic, structurally modified from clozapine to resist oxidation so as to reduce haematological and cardiological side effects. To assess the potential clinical potency of JL13 we tested its action in a newly described animal model based on the ability of clozapine-like agents to affect brain mechanisms controlling sympathetic outflow to thermoregulatory cutaneous vascular beds. We determined whether JL13 has clozapine-like inhibitory actions on alerting-induced falls in tail artery blood flow (sympathetic cutaneous vasomotor alerting responses, SCVARs) in rats, and whether actions on dopamine D(2), and/or 5-HT(1A) receptors are involved in these effects of JL13. The tail artery Doppler flow signal was recorded in conscious freely moving Sprague-Dawley rats before and after alerting stimuli (e.g. cage tap). The percentage fall in flow in response to an alerting stimulus was quantified as a SCVAR index (fall to zero flow implies SCVAR index of 100%, no fall implies 0%). We used pre-treatment with spiperone and WAY100635, before JL13, to assess the role of D(2) and 5-HT(1A) receptors. In addition, the role of 5-HT(2A) receptors in the action of JL13 was assessed by determining whether JL13 prevented and reversed the CNS-mediated tail artery vasoconstricting actions of DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), an agonist at 5-HT(2A) receptors. JL13 (0.0625-5.0mg/kg s.c.) dose-dependently inhibited SCVARs, less potently than clozapine. WAY100635 but not spiperone reduced the inhibition. JL13 prevented and reversed DOI-induced vasoconstriction. Thus JL13 has clozapine-like actions on thermoregulatory cutaneous blood flow, but the drug is 5 times less potent than clozapine. Stimulation of 5-HT(1A) and blockade of 5-HT(2A) receptors may contribute to the effects, but dopamine D(2) receptors are apparently not involved in the action of JL13.
authors.affiliation: Medicinal Chemistry & Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), Melbourne, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Capuano
authors.forename: I T
authors.initials: IT
authors.lastname: Crosby
authors.forename: F M
authors.initials: FM
authors.lastname: McRobb
authors.forename: D A
authors.initials: DA
authors.lastname: Taylor
authors.forename: A
authors.initials: A
authors.lastname: Vom
authors.forename: W W
authors.initials: WW
authors.lastname: Blessing
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D001833:Body Temperature Regulation / Q000187:drug effects*; D003024:Clozapine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007279:Injections, Subcutaneous / Q000379:methods; D017078:Laser-Doppler Flowmetry / Q000379:methods; D010077:Oxazepines / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D012044:Regression Analysis; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D012867:Skin / Q000098:blood supply* / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014666:Vasomotor System / Q000187:drug effects
chemical_list: C441720:5-(4-methylpiperazin-1-yl)-8-chloropyrido(2,3-b)(1,5)benzoxazepine fumarate; D010077:Oxazepines; D010879:Piperazines; D011725:Pyridines; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D003024:Clozapine