The antidepressant metapramine is a low-affinity antagonist at N-methyl-D-aspartic acid receptors.
Metapramine, a pharmacological compound with antidepressant activity in humans, was tested for possible antiglutamatergic activity, in vitro. We investigated the effects of metapramine on the N-methyl-D-aspartic acid (NMDA) receptor complex, by determining whether this compound would interfere with the binding of [3H]N-[1-(2-thienyl)cyclohexyl]-3,4-piperidine ([3H]TCP) to rat cortical membranes in the presence of either glycine NMDA, or both. Metapramine in the micromolar range inhibited the binding of [3H]TCP in the presence of both NMDA and glycine (IC50 = 1.4 +/- 0.2 microM). That very similar affinities were observed when either NMDA or glycine was present suggests that metapramine exerted a direct action at the PCP site. The affinity of metapramine for this site was about 25 and 350 times lower than that of PCP and MK-801, respectively. Metapramine inhibited the NMDA-evoked increase in guanosine 3',5'-cyclic monophosphate (cGMP) levels of neonatal rat cerebellar slices (IC50 = 13 microM). These results suggest that metapramine is a low-affinity antagonist of the NMDA receptor complex channel. This paper discusses the potential application of metapramine to the treatment of diseases linked to excessive stimulation of glutamatergic NMDA receptors.
Boireau
A
A
Rhône Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, Vitry-sur-Seine, France.
Bordier
F
F
Durand
G
G
Doble
A
A
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D003984:Dibenzazepines / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005998:Glycine / Q000378:metabolism; D066298:In Vitro Techniques; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology
D000929:Antidepressive Agents, Tricyclic; D003984:Dibenzazepines; D016194:Receptors, N-Methyl-D-Aspartate; C012677:metapramine; D016291:Dizocilpine Maleate; C012058:tenocyclidine; D006152:Cyclic GMP; D010622:Phencyclidine; D005998:Glycine