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.
Gaoni
Y
Y
Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, Israel.
Chapman
A G
AG
Parvez
N
N
Pook
P C
PC
Jane
D E
DE
Watkins
J C
JC
D000161:Acoustic Stimulation; D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000598:Amino Acids, Cyclic; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000627:therapeutic use; D001665:Binding Sites; D003198:Computer Simulation; D051379:Mice; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009046:Motor Neurons / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000209:etiology / Q000517:prevention & control; D013116:Spinal Cord / Q000378:metabolism; D013329:Structure-Activity Relationship
D000596:Amino Acids; D000598:Amino Acids, Cyclic; D000927:Anticonvulsants; D016194:Receptors, N-Methyl-D-Aspartate; C016987:1-aminocyclobutanecarboxylic acid