The pharmacology of SCH 50911: A novel, orally-active GABA-B receptor antagonist

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 274; no. 3; pp. 1393 - 1398
• Main Authors: Bolser, D C, Blythin, D J, Chapman, R W, Egan, R W, Hey, JA, Rizzo, C, Kuo, Shen-Chun, Kreutner, W
• Format: Journal Article
• Language: English
• Published: 1995
• Subjects: Rodentia
• ISSN: 0022-3565

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 (IC sub(50) = 1.1 mu M) than CGP 35348 (IC sub(50) = 62 mu M). SCH 50911 had no binding affinity for GABA-A, histamine H sub(1), histamine H sub(3), dopamine D sub(1), dopamine D sub(2), serotonin 5-HT sub(2), or muscarinic m1, m2, or m4 receptors. However, SCH 50911 (IC sub(50) = 2.2 mu M) 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 (pA sub(2) = 5.8 plus or minus 0.004). CGP 35348 was 19-fold less potent in this assay (pA sub(2) = 4.6 plus or minus 0.15). In vivo, SCH 50911 (ED sub(50) = 2.9 mg kg super(-1), s.c.) and CGP 35348 (ED sub(50) = 5.8 mg kg super(-1), s.c.) blocked the antitussive effects of baclofen in the guinea pig. In the cat, both SCH 50911 (10 mg kg super(-1), i.v.) and CGP 35348 (10 mg kg super(-1), i.v.) shifted the antitussive dose response relationship for baclofen to the right. Baclofen-induced respiratory depression was blocked by subcutaneous (ED sub(50) = 0.63 mg kg super(-1)), intraperitoneal (ED sub(50) = 1.9 mg kg super(-1)), or oral (ED sub(50) = 3 mg kg super(-1)) administration of SCH 50911. CGP 35348 also blocked the respiratory depressant effect of baclofen but was 3-9 fold less potent than SCH 50911 by these routes of administration. SCH 50911 (50 mu g, i.c.v.) completely blocked respiratory depression by baclofen indicating activity at GABA-B receptors in the CNS. The (-) enantiomer of SCH 50911 was inactive as a GABA-B antagonist. SCH 50911 is a selective, competitive, and orally active GABA-B receptor antagonist. Both central and peripheral GABA-B receptors are blocked by SCH 50911 and this antagonist is more potent than CGP 35348.