Relationship between structure, conformational flexibility, and biological activity of agonists and antagonists at the N-methyl-D-aspartic acid subtype of excitatory amino acid receptors
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Relationship between structure, conformational flexibility, and biological activity of agonists and antagonists at the N-methyl-D-aspartic acid subtype of excitatory amino acid receptors. / Madsen, U; Brehm, L; Schaumburg, Kjeld; Jørgensen, Flemming Steen; Krogsgaard-Larsen, P.
In: Journal of Medicinal Chemistry, Vol. 33, No. 1, 1990, p. 374-80.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Relationship between structure, conformational flexibility, and biological activity of agonists and antagonists at the N-methyl-D-aspartic acid subtype of excitatory amino acid receptors
AU - Madsen, U
AU - Brehm, L
AU - Schaumburg, Kjeld
AU - Jørgensen, Flemming Steen
AU - Krogsgaard-Larsen, P
PY - 1990
Y1 - 1990
N2 - The relationship between conformational flexibility and agonist or antagonist actions at the N-Methyl-D-aspartic acid (NMDA) subtype of central L-glutamic acid (GLU) receptors of a series of racemic piperidinedicarboxylic acids (PDAs) was studied. The conformational analyses were based on 1H NMR spectroscopy and supported by computer simulations and molecular mechanics calculations. While the trans forms of 2,3-PDA and 2,4-PDA and cis-2,5-PDA show NMDA receptor agonist activities, cis-2,3-PDA and cis-2,4-PDA are NMDA antagonists. The compounds trans-2,5-PDA and cis-2,6-PDA did not interact with NMDA receptors. Each of the three cyclic acidic amino acids showing NMDA agonist activities was found to exist as an equilibrium mixture of two conformers in aqueous solution. In contrast, the NMDA antagonists cis-2,3-PDA and cis-2,4-PDA as well as the inactive compounds trans-2,5-PDA and cis-2,6-PDA were shown to exist predominantly in a single conformation. These results seem to indicate that a certain degree of conformational flexibility of analogues of GLU is a prerequisite for activation of, but not for binding to, the NMDA receptor.
AB - The relationship between conformational flexibility and agonist or antagonist actions at the N-Methyl-D-aspartic acid (NMDA) subtype of central L-glutamic acid (GLU) receptors of a series of racemic piperidinedicarboxylic acids (PDAs) was studied. The conformational analyses were based on 1H NMR spectroscopy and supported by computer simulations and molecular mechanics calculations. While the trans forms of 2,3-PDA and 2,4-PDA and cis-2,5-PDA show NMDA receptor agonist activities, cis-2,3-PDA and cis-2,4-PDA are NMDA antagonists. The compounds trans-2,5-PDA and cis-2,6-PDA did not interact with NMDA receptors. Each of the three cyclic acidic amino acids showing NMDA agonist activities was found to exist as an equilibrium mixture of two conformers in aqueous solution. In contrast, the NMDA antagonists cis-2,3-PDA and cis-2,4-PDA as well as the inactive compounds trans-2,5-PDA and cis-2,6-PDA were shown to exist predominantly in a single conformation. These results seem to indicate that a certain degree of conformational flexibility of analogues of GLU is a prerequisite for activation of, but not for binding to, the NMDA receptor.
KW - 2-Amino-5-phosphonovalerate
KW - Animals
KW - Aspartic Acid
KW - Brain
KW - Computer Simulation
KW - Ibotenic Acid
KW - Kainic Acid
KW - Magnetic Resonance Spectroscopy
KW - Models, Molecular
KW - Molecular Conformation
KW - Molecular Structure
KW - N-Methylaspartate
KW - Pipecolic Acids
KW - Rats
KW - Receptors, N-Methyl-D-Aspartate
KW - Receptors, Neurotransmitter
KW - Stereoisomerism
KW - Structure-Activity Relationship
KW - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
U2 - 10.1021/jm00163a060
DO - 10.1021/jm00163a060
M3 - Journal article
C2 - 1967316
VL - 33
SP - 374
EP - 380
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 1
ER -
ID: 38394675