Characterization of D-3,4-cyclopropylglutamates as N-methyl-D-aspartate receptor agonists.
The 4 configurational isomers of D-3,4-cyclopropylglutamate (D-CGA) have been synthesized and analyzed for their interactions as excitatory amino acid recognition sites. Additionally, functional assessment of the action of these compounds at the N-methyl-D-aspartate (NMDA) receptor was performed. All 4 analogs function as agonists at the NMDA receptor as evidenced by their ability to stimulate [3H]MK-801 binding to the coupled PCP recognition site. Furthermore, the rank order of potency of these compounds in stimulating [3H]MK-801 binding corresponds with their Ki values for the displacement of NMDA-selective L-[3H]glutamate and [3H]CGS-19755 binding (D-CGA-C greater than D-CGA-B greater than D-CGA-D greater than D-CGA-A). The D-CGA-C isomer has affinity and potency at the NMDA receptor similar to the endogenous agonist, L-glutamate. This high potency coupled with greater specificity than L-glutamate, makes D-CGA-C a potentially useful pharmacological tool for the study of this receptor.
Monahan
J B
JB
Central Nervous System Diseases Research, G.D. Searle and Co., St. Louis, MO 63198.
Hood
W F
WF
Compton
R P
RP
Cordi
A A
AA
Snyder
J P
JP
Pellicciari
R
R
Natalini
B
B
D000600:Amino Acids, Dicarboxylic / Q000378:metabolism*; D000818:Animals; D003986:Dibenzocycloheptenes / Q000378:metabolism*; D016291:Dizocilpine Maleate; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D013237:Stereoisomerism
D000600:Amino Acids, Dicarboxylic; D003986:Dibenzocycloheptenes; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C035261:(alpha-carboxycyclopropyl)glycine; D016291:Dizocilpine Maleate