N-methyl-D-aspartate receptor-mediated contractions of the guinea pig ileum longitudinal muscle/myenteric plexus preparation: modulation by phencyclidine and glycine receptors.
Glutamate evoked contractions of the longitudinal muscle/myenteric plexus (LMMP) preparation by an action at N-methyl-D-aspartate (NMDA) receptors. Other agonists at the NMDA recognition site, but not quisquilate or kainate, also contracted the LMMP, and glutamate-evoked contractions were competitively inhibited by selective NMDA receptor antagonists. Glutamate-evoked contractions were noncompetitively inhibited by MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine moleate], phencyclidine (PCP) and other compounds that bind to the PCP receptor, which is a binding site on the NMDA channel complex. Their potencies for this effect were highly correlated with their affinities for the PCP receptor. Glycine significantly shifted the glutamate concentration-response curve to the left. Glycine site antagonists caused a glycine-sensitive, noncompetitive inhibition of glutamate-evoked contractions, and their potencies for this effect were highly correlated with their affinities for the glycine binding site of the NMDA channel complex. Mg++ and Zn++ also noncompetitively inhibited glutamate-evoked contractions. The modulatory effects of glycine, Mg++, Zn++ and PCP receptor ligands were specific to glutamate-evoked contractions. MK-801 was highly selective for inhibition of glutamate-evoked contractions; MK-801 also inhibited nicotinic responses at a 500-fold lower potency. Two novel compounds are described that bind to the PCP receptor with high affinity and selectively inhibit glutamate-evoked contractions in the LMMP.
Department of Physiology, Oregon Health Sciences University, Portland.
B G
BG
Campbell
P
P
Couceyro
J F
JF
Keana
E
E
Weber
D000818:Animals; D001921:Brain / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists; D005260:Female; D005971:Glutamates / Q000494:pharmacology*; D018698:Glutamic Acid; D005998:Glycine / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D017478:Receptors, Phencyclidine
D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D017478:Receptors, Phencyclidine; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D005998:Glycine