Alan L. Mueller

NPS 1506, A Novel NMDA Receptor Antagonist and Neuroprotectant: Review of Preclinical and Clinical Studies

ABSTRACT: NPS 1506 is a moderate affinity, uncompetitive N‐methyl‐d‐aspartate (NMDA) receptor antagonist. NPS 1506 is neuroprotective in rodent models of ischemic stroke, hemorrhagic stroke, and head trauma, with a 2‐hr window of opportunity. Neuroprotectant doses of NPS 1506 ranged from approximately 0.1–1.0 mg/kg, with peak plasma concentrations ranging from 8–80 ng/mL. Even at doses producing behavioral toxicity, NPS 1506 did not elicit MK‐801‐like behaviors, did not generalize to phencyclidine (PCP), and did not elicit neuronal vacuolization.

Chiral synthesis and pharmacological evaluation of NPS 1407 : A potent, stereoselective NMDA receptor antagonist

The stereoselective synthesis and biological activity of NPS 1407 (4a), (S)-(-)-3-amino-1,1-bis(3-fluorophenyl)butane, a potent, stereoselective antagonist of the NMDA receptor, are described. The racemate (4) was found to be active at the NMDA receptor in an in vitro assay, prompting the synthesis of the individual stereoisomers. The S isomer (4a) was found to be 12 times more potent than the R isomer (4b). Compound 4a demonstrated in vivo pharmacological activity in neuroprotection and anticonvulsant assays.

Design, synthesis, and biological evaluation of spider toxin (argiotoxin-636) analogs as NMDA receptor antagonists.

AbstractPurpose. Twelve synthetic spider toxin analogs were prepared in an effort to better understand the structure-activity relationships of the polyamine portion of argiotoxin-636 (Arg-636), a noncompetitive NMDA receptor (NMDAR) antagonist. Methods. The l,13-diamino-4,8-diazatridecane portion of the side chain of Arg-636 was systematically modified in an effort to further our knowledge of the structural requirements for the alkyl linker spacing between the amine nitrogens. Systematic isosteric replacement of each of the amine nitrogens in the polyamine moiety with either oxygen or carbon provided a series of compounds which were evaluated in vitro for NMDAR antagonist activity. Results. One-half of the heteroatoms found in Arg-636 were removed to provide analogs which maintained in vitro potency below 1 μM. However, these simplified analogs produced similar or more pronounced effects on the cardiovascular system than Arg-636 in vivo. Conclusions. In this set of analogs, a minimum of three basic nitrogens in the side chain was required for maximum potency as NMDAR antagonists. Isosteric nitrogen substitutions in the polyamine chain reduced the in vitro potency of these analogs. An analog binding-conformation model was proposed to rationalize the inactivity of these isosterically substituted analogs.

Synthesis, biological activity, and absolute stereochemical assignment of NPS 1392 : A potent and stereoselective NMDA receptor antagonist

The synthesis, biological activity, and single crystal X-ray structure of NPS 1392, (R)-(-)-3,3-bis(3-fluorophenyl)-2-methylpropan-1-amine (3a), a potent, stereoselective antagonist of the NMDA receptor, are described. The NMDA receptor selectively bound the levo isomer (3a) over its enantiomer (3b), which prompted a rigorous absolute configuration assignment. NPS 1392 has the R configuration based on the single-crystal X-ray diffraction analysis of the hydroiodide salt of NPS 1392. This compound is a potential neuroprotective agent for use in the treatment of ischemic stroke.