Synthesis, NMDA receptor antagonist activity, and anticonvulsant action of 1-aminocyclobutanecarboxylic acid derivatives

A range of cis- and trans-3-substituted 1-aminocyclobutane-1-carboxylic acids has been synthesized and evaluated for antagonism at excitatory amino acid receptor sites and for anticonvulsant activity. Potent and selective antagonist activity at N-methyl-D-aspartate (NMDA) receptor sites in neonatal rat motoneurones was shown by compounds in which the 3-substituent was, or contained, a 2'-carboxyethyl or 2'-phosphonoethyl moiety. Substances 4b, 24, 35, and 40 were more potent than the standard NMDA Receptor Antagonist, D-2-amino-5-phosphonopentanoate (D-AP5) as NMDA antagonists in this preparation, and about equipotent with [3-(+/-)-2-carboxypiperazin-4-yl)-1-propyl]phosphonate (CPP). Anticonvulsant activity, as assessed following intracerebroventricular injection into audiogenic DBA/2 mice, generally paralleled NMDA Receptor Antagonist activity.