title: McN-5652: a highly potent inhibitor of serotonin uptake.
abstract: McN-5652 is one of a series of substituted pyrrolo-isoquinolines that, as a group, potently inhibit the uptake of one or more of the monoamines, norepinephrine, serotonin and dopamine. McN-5652 is characterized by exceptionally high potency as an inhibitor of the uptake of serotonin by rat brain synaptosomes in vitro (Ki approximately 0.6 nM) and ex vivo (ED50 approximately 2 mg/kg p.o.). The high potency of McN-5652 as a serotonin uptake inhibitor in vivo is indicated further by the low doses required to potentiate L-5-hydroxytryptophan-induced head twitches in mice (ED50 = 0.4 mg/kg 2 hr after p.o. dosing) and the serotonin syndrome in rats (ED50 = 1.5 mg/kg 2 hr after p.o. dosing). McN-5652 also potently inhibited the synaptosomal uptake of norepinephrine (Ki approximately 3 nM) and was a moderately potent inhibitor of the synaptosomal uptake of dopamine (Ki approximately 40 nM). McN-5652 inhibited tetrabenazine-induced ptosis in rats and mice but was much less effective in blocking the sedation caused by tetrabenazine. In rats, McN-5652 did not induce the stereotyped behavior often caused by dopamine agonists and inhibitors of dopamine uptake. Receptor binding experiments indicated that McN-5652 has a weak affinity for serotonin 5-HT2 and alpha-1 adrenergic receptors (apparent Ki approximately 200 nM) and a very low affinity for dopamine D1 and D2 receptors, serotonin 5-HT1, alpha-2 adrenergic, muscarinic and gamma-aminobutyric acid-A receptors. Experiments using the guinea pig ileum indicate that McN-5652 is a weak, noncompetitive antagonist of histamine.
authors.affiliation: Department of Biological Research, McNeil Pharmaceutical, Spring House, Pennsylvania.
authors.forename: R P
authors.initials: RP
authors.lastname: Shank
authors.forename: J L
authors.initials: JL
authors.lastname: Vaught
authors.forename: K A
authors.initials: KA
authors.lastname: Pelley
authors.forename: P E
authors.initials: PE
authors.lastname: Setler
authors.forename: D F
authors.initials: DF
authors.lastname: McComsey
authors.forename: B E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D010276:Parasympatholytics / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D013239:Stereotyped Behavior / Q000187:drug effects; D013747:Tetrabenazine / Q000494:pharmacology
chemical_list: D000928:Antidepressive Agents; D006634:Histamine H1 Antagonists; D007546:Isoquinolines; D014179:Neurotransmitter Uptake Inhibitors; D010276:Parasympatholytics; D011985:Receptors, Serotonin; D012701:Serotonin; C058079:McN 5652; D006916:5-Hydroxytryptophan; D004298:Dopamine; D013747:Tetrabenazine