BEHAVIORAL PHARMACOLOGY OF NPC-17742, A COMPETITIVE N-METHYL-D-ASPARTATE (NMDA) ANTAGONIST

The behavioral effects of the competitive N-methyl-D-aspartate (NMDA) antagonist 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoate (NPC 177 42) were compared with those of its parent compound, 2-amino-4,5-(1,2- cyclohexyl)-7-phosphonoheptanoate (NPC 12626), and other reference age nts in a variety of operant-based tasks in rodents. In mice trained to lever press under a fixed-ratio (FR) 20 reinforcement schedule, NPC 1 7742 was 6.2 times more potent than NPC 12626 and equipotent with the competitive NMDA antagonist [E]-2-amino-4-methyl-5-phosphono-3-pentene oic acid (CGP 37849) in reducing rates of responding. NPC 17742 was al so 3.5 and 4.5 times more potent than [+/-]cis-4-phosphonomethyl-2-pip eridine carboxylate (CGS 19755) and [+/-] 3-(2-carboxypiperazin-4-yl)p ropyl-1-phosphonate (CPP), respectively, and half as potent as 3SR, 4a RS, 6SR, ,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (LY 274614 ) in this paradigm. In rats trained to discriminate 4.0 mg/kg NPC 1774 2 from saline, NPC 17742 was 5.7 times more potent than NPC 12626 in s ubstituting for NPC 17742. CGS 19755 also substituted for NPC 17742, b ut a maximum of only 50% NPC 17742 lever responding was observed after LY 274614 administration. In rats trained to lever press in a modifie d Geller-Seifter procedure, NPC 17742 and NPC 12626, like the benzodia zepine chlordiazepoxide, increased rates of punished responding. Neith er tolerance nor sensitization to the antipunishment effects were obse rved upon administration of NPC 17742 for 5 consecutive days. The resu lts are consistent with NPC 17742 being a potent, systemically active compound whose behavioral effects are mediated through interaction wit h the NMDA receptor. Additionally, the results support the notion that competitive NMDA antagonists represent a novel class of compounds act ive in the preclinical assessment of antianxiety agents. Furthermore, competitive NMDA antagonists may not represent a homogeneous group of compounds with regard to their discriminative stimulus effects.