(3R,4S)-3-[4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol:  A Conformationally Restricted Analogue of the NR2B Subtype-Selective NMDA Antagonist (1S,2S)-1-(4-Hydroxyphenyl)-2- (4-hydroxy-4-phenylpiperidino)-1-propanol

Abstract

(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606, 1) is a recently described antagonist of N-methyl-D-aspartate (NMDA) receptors containing the NR2B subunit. In the present study, the optimal orientation of compounds of this structural type for their receptor was explored. Tethering of the pendent methyl group of 1 to the phenolic aromatic ring via an oxygen atom prevents rotation about the central portion of the molecule. Several of the new chromanol compounds have high affinity for the racemic [3H]CP-101,606 binding site on the NMDA receptor and protect against glutamate toxicity in cultured hippocampal neurons. The new ring caused a change in the stereochemical preference of the receptor-cis (erythro) compounds had better affinity for the receptor than the trans isomers. Computational studies suggest that steric interactions between the pendent methyl group and the phenol ring in the acyclic series determine which structures can best fit the receptor. The chromanol analogue, (3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1- yl]chroman-4,7-diol (12a, CP-283,097), was found to possess potency and selectivity comparable to CP-101,606. Thus 12a is a new tool to explore the function of the NR2B-containing NMDA receptors.

Characterisation of N‐Methyl‐D‐Aspartate Receptor‐Specific [3H]Ifenprodil Binding to Recombinant Human NR1a/NR2B Receptors Compared with Native Receptors in Rodent Brain Membranes

“…The affinity values obtained for the ifenprodil site ligands eliprodil, (Ϯ)-CP-101,606, (Ϯ)-CP-283,097, and (Ϯ)-Ro 25-6981 were very comparable to those previously reported for inhibition of [ 3 H]CP-101,606 (Menniti et al, 1997;Butler et al, 1998) and [ 3 H]Ro 25-6981 binding to rat forebrain membranes. Ifenprodil displaced [ 3 H]ifenprodil binding to rat brain membranes with similar affinity to that reported using [ 3 H]CP-101,606 (Menniti et al, 1997) and [ 3 H]Ro 25-6981 but showed fivefold weaker activity against [ 3 H]ifenprodil binding to NR1a/NR2B receptors (Table 2a).…”

“…The affinity values obtained for the ifenprodil site ligands eliprodil, (Ϯ)-CP-101,606, (Ϯ)-CP-283,097, and (Ϯ)-Ro 25-6981 were very comparable to those previously reported for inhibition of [ 3 H]CP-101,606 (Menniti et al, 1997;Butler et al, 1998) …”

“…Recently, several NR2B-selective compounds have been described, including (R *,R *)-4-hydroxy-␣-(4hydroxyphenyl)-␤-methyl-4-phenyl-1-piperidineethanol (CP-101,606) (Chenard et al, 1995), cis-3-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]-3,4-dihydro-2H-1-benzopyran-4,7-diol (CP-283,097) (Butler et al, 1998), and (R*,S*)-␣-(4-hydroxyphenyl)-␤-methyl-4-(phenylmethyl)-1-piperidinepropanol (Ro 25-6981) (Fischer et al, 1997). These compounds are closely related to the phenylethanolamine ifenprodil, which was first described as an NMDA receptor antagonist in 1988 (Carter et al, 1988) and more recently found to be NR2B subtype-selective (Williams, 1993).…”

Synaptic mechanisms in nociception: emerging targets for centrally-acting analgesics

“…Elsewhere, this subtype appears to be limited to the forebrain. CP-101,606 [73] and Ro 25-6981 [74] are derivatives of ifenprodil that are potent and selective antagonists for receptors containing the NR2B subunit, and both have been shown to reduce allodynia in a rat model of nerve-injury pain at doses 10 -100 times lower than those which induce motor deficits [67]. Furthermore, felbamate, a novel anticonvulsant drug that has been found to be highly effective in animal models of neuropathic pain [75,76], is a selective antagonist of NR2B-containing receptors [77].…”

“…These data are very promising, and a number of other NR2B selective antagonists have been developed recently by Pfizer, Parke-Davis and CoCensys, and Novartis [78][79][80][81][82][83][84][85][86]. Amongst the compounds so far developed, CO 101244/PD 174494 shows good selectivity coupled with high potency and in vivo activity [78], while CP-283,097 shares these features and possesses oral availability [73]. Finally, the conantokins, venoms derived from cone snails (curiously the same animals that gave us the N-type calcium channel blocker, ziconotide [see below]), have been shown indirectly to possess some selectivity between NMDA receptor subtypes [87] and have been claimed to show a good analgesic profile [88].…”