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In vivo binding of SCH 39166: a D-1 selective antagonist

RD McQuade, RA Duffy, VL Coffin, RE Chipkin and A Barnett

Schering-Plough Research, Bloomfield, New Jersey.

SCH 39166 [(-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N- methyl- 5H-benzo[d]naphtho-[2,1b]-azepine] has been identified previously as a potent and selective D-1 antagonist. These studies demonstrated that SCH 39166 binds to the D-1 receptor in vitro and inhibits the rat conditioned avoidance response, a test predictive of antipsychotic activity. The current study demonstrates that SCH 39166 inhibits the in vivo binding of [125I]SCH 38840 to D-1 receptors in rat striatal tissue with an ED50 of 11.67 nmol/animal or 0.016 mg/kg s.c. SCH 39166 did not inhibit the in vivo binding of [125I]SCH 38840 to rat frontal cortex, suggesting that, unlike other D-1 antagonists, SCH 39166 was not binding to 5-hydroxytryptamine (5-HT)2 receptors in vivo. The in vivo binding of SCH 39166 to D-2 receptors was studied using [3H]raclopride and demonstrated that SCH 39166 did not bind to D-2 receptors up to doses of 100 mumol/animal or approximately 150 mg/kg s.c. Further studies to determine the in vivo selectivity of SCH 39166 utilized N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) to inactivate selected neurotransmitter receptors. Preadministration of SCH 39166, at doses as low as 0.01 mg/kg s.c., produced a statistically significant protection of D-1 receptors from EEDQ inactivation. SCH 39166 produced a similar protection of 5-HT2 receptors only at the highest dose tested, 10 mg/kg s.c., whereas there was no protection of D-2 sites even at this high dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 257, Issue 1, pp. 42-49, 04/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1991 by the American Society for Pharmacology and Experimental Therapeutics.