title: Pharmacological characterization of interactions of RO 25-6981 with the NR2B (epsilon2) subunit.
abstract: We used ligand binding to ascertain whether the pharmacological actions of RO 25-6981 [(R:(*), S:(*))-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidinepropanol] match those of other NR2B (epsilon2) subunit specific agents. RO 25-6981 inhibited binding of 125I-MK801 [iodo-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohept-5,10-imine maleate] to receptors made from NR1a/epsilon2 but not NR1a/epsilon1. Increasing the concentration of spermidine did not change the efficacy of RO 25-6981 and minimally changed the IC(50) value. Chimeric epsilon1/epsilon2 receptors demonstrated that the structural determinants for high affinity actions of RO 25-6981 were contained completely within the first 464 amino acids, but no receptor retained wildtype features when the size of the epsilon2 component was decreased further. Epsilon1Q336R receptors were more inhibited by ifenprodil and RO 25-9681 than wildtype epsilon1 receptors in ligand binding assays but not in functional assays. Selected mutations of epsilon2E200 and epsilon2E201 also decreased the sensitivity of receptors to ifenprodil and RO 25-6981. These results suggest that RO 25-6981 shares structural determinants with ifenprodil and other modulators in the NR2B subunit.
authors: Department of Neurology, University of Pennsylvania School of Medicine, Children's Seashore House, Philadelphia, PA 19104, USA. lynch@pharm.med.upenn.edu
authors: D R
authors: DR
authors: Lynch
authors: S S
authors: SS
authors: Shim
authors: K M
authors: KM
authors: Seifert
authors: S
authors: S
authors: Kurapathi
authors: V
authors: V
authors: Mutel
authors: M J
authors: MJ
authors: Gallagher
authors: R P
authors: RP
authors: Guttmann
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D051379:Mice; D009154:Mutation; D010636:Phenols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011869:Radioligand Assay; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013095:Spermidine / Q000494:pharmacology
chemical_list: D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D010636:Phenols; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; C109643:Ro 25-6981; D016291:Dizocilpine Maleate; D006220:Haloperidol; C010739:ifenprodil; D013095:Spermidine