THE PHARMACOLOGY OF SCH-50911 - A NOVEL, ORALLY-ACTIVE GABA-B RECEPTOR ANTAGONIST

Experiments were conducted to characterize the pharmacology of SCH 509 11 ((+)-5, 5-dimethyl-2-morpholineacetic acid hydrochloride), a struct urally novel GABA-B receptor antagonist. Although more potent GABA-B a ntagonists have been reported, in this study SCH 50911 was compared wi th 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 mu M) than CGP 35348 (IC50 = 62 mu M. SCH 50911 had no binding affinity for GABA-A, histamine H-1, histamine H-3, dopamine D-1, dopamine D-2, ser otonin 5-HT2, or muscarinic m1, m2, or m4 receptors. However, SCH 5091 1 (IC50 = 2.2 mu M) was active in a nonspecific muscarinic receptor bi nding assay, but was devoid of muscarinic agonist or antagonist activi ty in the isolated guinea pig ileum. SCH 50911 blocked inhibitory resp onses to baclofen of the guinea pig trachea in a competitive manner (p A(2) = 5.8 +/- 0.004). CGP 35348 was 19-fold less potent in this assay (pA(2) = 4.6 +/- 0.15). In vivo, SCH 50911 (ED(50) = 2.9 mg kg(-1), s .c.) and CGP 35348 (ED(50) = 5.8 mg kg(-1), s.c.) blocked the antituss ive 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 an titussive dose response relationship for baclofen to the right. Baclof en-induced respiratory depression was blocked by subcutaneous (ED(50) = 0.63 mg kg(-1)), intraperitoneal (ED(50) = 1.9 mg kg(-1)), or oral ( ED(50) = 3 mg kg(-1)) administration of SCH 50911. CGP 35348 also bloc ked the respiratory depressant effect of baclofen but was 3-9 fold les s potent than SCH 50911 by these routes of administration. SCH 50911 ( 50 <mu.g, i.c.v.) completely blocked respiratory depression by baclofe n indicating activity at GABA-B receptors in the CNS. The (-) enantiom er of SCH 50911 was inactive as a GABA-B antagonist. SCH 50911 is a se lective, competitive, and orally active GABA-B receptor antagonist. Bo th central and peripheral GABA-B receptors are blocked by SCH 50911 an d this antagonist is more potent than CGP 35348.