Discovery of new SCH 39166 analogs as potent and selective dopamine D1 receptor antagonists.
ABSTRACT A series of novel dopamine D(1) antagonists derived from functionalization of the D-ring of SCH 39166 were prepared. A number of these compounds displayed subnanomolar D(1) activity and more than 1000-fold selectivity over D(2). We found C-3 derivatization afforded compounds with superior overall profile in comparison to the C-2 and C-4 derivatization. A number of highly potent D(1) antagonists were discovered which have excellent selectivity over other dopamine receptors and improved PK profile compared to SCH 39166.
Article: Multiple receptors for dopamine.[show abstract] [hide abstract]
ABSTRACT: Pharmacological and biochemical criteria can be used to separate those dopamine receptors which are linked to the enzyme adenylyl cyclase and those which are not.Nature 02/1979; 277(5692):93-6. · 38.60 Impact Factor
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ABSTRACT: SCH 23390 [R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) possesses pharmacologic effects similar to standard antipsychotics, including selective supression of conditioned avoidance responding in rats and squirrel monkeys, blockade of apomorphine-induced stereotypy in rats and blockade of methamphetamine-induced lethality in aggregated mice. At effective doses in these tests, no changes in gross behavior, neurological or autonomic function were observed. In contrast to the standards tested, SCH 23390 blocked dopamine-stimulated adenylate cyclase at concentrations (IC50 = 0.01 microM) about 2000 times lower than those needed to block spiperone binding (IC50 = 24 microM). This suggests specific D1-receptor antagonism. Inability of SCH 23390 to cause hyperprolactinemia, considered to be a D2-receptor effect, is consistent with this hypothesis. SCH 23390 showed lower increases in dopamine turnover suggesting that the blockade of SCH 23390 may be more specific for post- than presynaptic sites. Additional evidence for the selectivity of SCH 23390 among putative postsynaptic dopamine sites includes its lack of effect on apomorphine-induced hypothermia or emesis. Based on these results, it is postulated that SCH 23390 is a selective D1-receptor antagonist.Journal of Pharmacology and Experimental Therapeutics 09/1983; 226(2):462-8. · 3.89 Impact Factor