Characterization of 3-carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline (SC-48981), a potent competitive N-methy-D-aspartate (NMDA) receptor antagonist, in vitro and in vivo.
(+/-)-3-Carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline (SC-48981), a conformationally restricted analog of the potent competitive N-methyl-D-aspartate (NMDA) antagonist, 2-amino-5-phosphonopentanoate (AP-5), potently inhibited the binding of [3H]glutamate to the N-methyl-D-aspartate (NMDA) receptors with a Ki of 1.6 mcM, but with minimal affinity for kaininate and quisqualate receptors (Ki greater than 50 mcM), in vitro. Consistent with its ability to antagonize the NMDA receptor, SC-48981 decreased the binding of [3H]glycine and [3H]TCP [1-(2-thienyl)cyclohexylpiperidine] to the NMDA-associated glycine and phencyclidine (PCP) recognition sites, in vitro. SC-48981 attenuated levels of basal cGMP and harmaline-induced increases in levels of cGMP in the mouse cerebellum, in vivo, in a competitive manner, with ED50 values of 5.5 and 8.7 mg/kg, i.p. Direct intracerebellar injection of SC-48981 (0.5 microgram) attenuated increases in levels of cGMP induced by central injection of the NMDA-associated glycine receptor agonist, D-serine and by NMDA itself. Parenteral administration of SC-48981 (25 mg/kg, s.c.) decreased basal levels of cGMP for up to 3 h. These results indicate that SC-48981 represents a novel bioavailable competitive NMDA antagonist with a long duration of action.
Searle Research and Development, G.D. Searle & Co., St. Louis, MO 63198.
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Vazquez
D J
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Garland
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Sun
J A
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Cler
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Mick
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Hood
J B
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Monahan
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Iyengar
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Rao
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D005998:Glycine / Q000378:metabolism; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044005:Tetrahydroisoquinolines
D005971:Glutamates; D007546:Isoquinolines; D009943:Organophosphorus Compounds; D016194:Receptors, N-Methyl-D-Aspartate; D044005:Tetrahydroisoquinolines; C075508:3-carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline; D018698:Glutamic Acid; D016202:N-Methylaspartate; C012058:tenocyclidine; D006152:Cyclic GMP; D010622:Phencyclidine; D005998:Glycine