ROPHENYL)-4-HYDROXYPIPERIDIN-1-YL]CHROMAN-4,7-DIOL - A CONFORMATIONALLY RESTRICTED ANALOG OF THE NR2B SUBTYPE-SELECTIVE NMDA ANTAGONIST PHENYL)-2(4-HYDROXY-4-PHENYLPIPERIDINO)-1-PROPANOL

henyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606, 1) is a recently described antagonist of N-methyl-D-aspartate (NMDA) recepto rs containing the NR2B subunit. In the present study, the optimal orie ntation of compounds of this structural type for their receptor was ex plored. Tethering of the pendent methyl group of 1 to the phenolic aro matic ring via an oxygen atom prevents rotation about the central port ion of the molecule. Several of the new chromanol compounds have high affinity for the racemic [H-3]CP-101,606 binding site on the NMDA rece ptor and protect against glutamate toxicity in cultured hippocampal ne urons. The new ring caused a change in the stereochemical preference o f the receptor-cis (erythro) compounds had better affinity for the rec eptor than the trans isomers. Computational studies suggest that steri c interactions between the pendent methyl group and the phenol ring in the acyclic series determine which structures can best fit the recept or. The chromanol analogue, rophenyl)-4-hydroxypiperidin-1-yl]chroman- 4,7-diol (12a, CP-283,097), was found to possess potency and selectivi ty comparable to CP-101,606. Thus 12a is a new tool to explore the fun ction of the NR2B-containing NMDA receptors.