title: The pharmacology of SCH 50911: a novel, orally-active GABA-beta receptor antagonist.
abstract: Experiments were conducted to characterize the pharmacology of SCH 50911 ((+)-5,5-dimethyl-2-morpholineacetic acid hydrochloride), a structurally novel GABA-B receptor antagonist. Although more potent GABA-B antagonists have been reported, in this study SCH 50911 was compared with CGP 35348, a moderately potent and selective GABA-B antagonist with acceptable in vivo activity. SCH 50911 was more potent to inhibit the binding of GABA to the GABA-B receptor in rat brain (IC50 = 1.1 microM) than CGP 35348 (IC50 = 62 microM). SCH 50911 had no binding affinity for GABA-A, histamine H1, histamine H3, dopamine D1, dopamine D2, serotonin 5-HT2, or muscarinic m1, m2, or m4 receptors. However, SCH 50911 (IC50 = 2.2 microM) was active in a nonspecific muscarinic receptor binding assay, but was devoid of muscarinic agonist or antagonist activity in the isolated guinea pig ileum. SCH 50911 blocked inhibitory responses to baclofen of the guinea pig trachea in a competitive manner (pA2 = 5.8 +/- 0.004). CGP 35348 was 19-fold less potent in this assay (pA2 = 4.6 +/- 0.15). In vivo, SCH 50911 (ED50 = 2.9 mg kg-1, s.c.) and CGP 35348 (ED50 = 5.8 mg kg-1, s.c.) blocked the antitussive effects of baclofen in the guinea pig. In the cat, both SCH 50911 (10 mg kg-1, i.v.) and CGP 35348 (10 mg kg-1, i.v.) shifted the antitussive dose response relationship for baclofen to the right.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Schering-Plough Research Institute, Kenilworth, New Jersey, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Bolser
authors.forename: D J
authors.initials: DJ
authors.lastname: Blythin
authors.forename: R W
authors.initials: RW
authors.lastname: Chapman
authors.forename: R W
authors.initials: RW
authors.lastname: Egan
authors.forename: J A
authors.initials: JA
authors.lastname: Hey
authors.forename: C
authors.initials: C
authors.lastname: Rizzo
authors.forename: S C
authors.initials: SC
authors.lastname: Kuo
authors.forename: W
authors.initials: W
authors.lastname: Kreutner
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000996:Antitussive Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001418:Baclofen / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016466:CHO Cells; D002415:Cats; D018678:Cholinergic Agents / Q000494:pharmacology; D006224:Cricetinae; D018756:GABA Antagonists / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D058788:GABA-B Receptor Antagonists; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000378:metabolism; D014132:Trachea / Q000187:drug effects / Q000502:physiology
chemical_list: C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; D000996:Antitussive Agents; D018678:Cholinergic Agents; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D009025:Morpholines; D018080:Receptors, GABA-B; D001418:Baclofen