HENYL)-2-(4-HYDROXY-4-PHENYLPIPERIDINO)-1-PROPANOL - A POTENT NEW NEUROPROTECTANT WHICH BLOCKS N-METHYL-D-ASPARTATE RESPONSES

henyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (20, CP-101,606) ha s been identified as a potent and selective N-methyl-D-aspartate NMDA) antagonist through a structure activity relation (SAR) program based on ifenprodil, a known antihypertensive agent with NMDA antagonist act ivity. Sites on the threo-ifenprodil skeleton explored in this report include the pendent methyl group (H, methyl, and ethyl nearly equipote nt; propyl much weaker), the spacer group connecting the C-4 phenyl gr oup to the piperidine ring (an alternating potency pattern with 0 and 2 carbon atoms yielding the greatest potency), and simple phenyl subst itution (little effect). While potent NMDA antagonists were obtained w ith a two atom spacer, this arrangement also increased al adrenergic a ffinity. Introduction of a hydroxyl group into the C-4 position on the piperidine ring resulted in substantial reduction in alpha(1) adrener gic affinity. The combination of these observations was instrumental i n the discovery of 20. This compound potently protects cultured hippoc ampal neurons from glutamate toxicity (IC50 = 10 nM) while possessing little of the undesired al adrenergic affinity (IC50 similar to 20 mu M) of ifenprodil. Furthermore, 20 appears to lack the psychomotor stim ulant effects of nonselective competitive and channel-blocking NMDA an tagonists. Thus, 20 shows great promise as a neuroprotective agent and may lack the side effects of compounds currently in clinical trials.