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

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

SN - 0022-2623

VL - 33

SP - 374

EP - 380

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 1

ER -