Indole-2-carboxylates, novel antagonists of the N-methyl-D-aspartate (NMDA)-associated glycine recognition sites: in vivo characterization.

Recent in vitro receptor binding studies have indicated that indole-2-carboxylates with halogen substitutions at the position 5 or 6 are potent competitive antagonists of the NMDA (N-methyl-D-aspartate)-associated strychnine-insensitive glycine receptor (Gray N. M., Dappen M.

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.

Actions of D-cycloserine at the N-methyl-D-aspartate-associated glycine receptor site in vivo.

The antibiotic, D-cycloserine has been shown to be a partial agonist at the N-methyl-D-aspartate (NMDA)-coupled, strychnine-insensitive glycine receptor by in vitro receptor binding. This partial agonism was further investigated in an in vivo system, by monitoring changes in levels of cyclic guanosine-monophosphate (cGMP), a well characterized second messenger response, mediated by the NMDA receptor complex, in the cerebellum of the mouse. Parenteral injections of D-cycloserine produced a biphasic dose-response curve which suggested partial agonism.

Effects of sigma ligands on mouse cerebellar cyclic guanosine monophosphate (cGMP) levels in vivo: further evidence for a functional modulation of N-methyl-D-aspartate (NMDA) receptor complex-mediated events by sigma ligands.

In the present investigation, the effects of sigma ligands [WY-47384 [8-fluoro-2,3,4,5-tetrahydro-2[3-(3-pyridinyl)propyl)1H- pyrido(4,3b)indole], (+)-pentazocine, (+)-SFK 10,047 (N-allylnormetazocine), mafoprazine, opipramol, dextromethorphan, dextrorphan, (+)-3-PPP [3-(3-hydroxyphenyl)-N-propylpiperidine], (-)-butaclamol, DTG [1,3-di(2-tolyl)guanidine], rimcazole, ifenprodil and BMY-14802 [alpha-(fluorophenyl)-4-(5-fluoropyrimidinyl)-1-piperazine butanol]] on harmaline-, pentylenetetrazol (PTZ)-, methamphetamine (MA)- and D-serine-induced increases in mouse cerebellar levels of cGMP were determined. Ifenprodil, BMY-14802, dextromethorphan, dextrorphan, (+)-SKF 10,047, opipramol and mafoprazine reversed harmaline-, PTZ-, MA- and D-serine-induced increases in levels of cGMP. Rimcazole reversed only the harmaline-induced response.

Clozapine attenuates N-methyl-D-aspartate receptor complex-mediated responses in vivo: tentative evidence for a functional modulation by a noradrenergic mechanism.

Recent studies revealed a role for dopamine and noradrenaline in the etiology of ischemia-induced neuronal cell death. In the present investigation, the modulation by clozapine, an atypical antipsychotic agent that interacts with adrenergic receptors, of N-methyl-D-aspartate (NMDA) receptor complex-mediated events were studied by examining its effects on levels of cGMP in the cerebellum. Clozapine decreased basal levels of cGMP in the cerebellum and antagonized harmaline-, methamphetamine-, pentylenetetrazol- and D-serine-induced increases in levels of cGMP with ED50 values of 3.