Structure-activity relationship on excitatory amino acid receptors.
It is generally accepted that the carboxylic amino acids L-Glu and L-Asp play a role as excitatory neurotransmitters at the CNS. In the search of a structure-activity relationship we have made a theoretical conformational analysis with a mechanics molecular model on active compounds on QUIS and NMDA-receptors. We consider the COO-...COO- distance in these compounds as the more important one in order to discuss the different mode of action of this compound at the excitatory amino acid receptors. On QUIS-receptors: We had found that Glu, Asp and QUIS are very flexible molecules that can easily pass from one conformation to another and to get the distance of 3A degrees between the two COO- groups. All these compounds show an important population in conformations with this distance. The antagonist GDEE had 90% of its whole population in folded conformations with a distance of about 3 A degrees between COO-...COO- groups. On NMDA-receptors: IBO is a rigid analogue and the distance COO-...COO- is about 4A degrees at the different conformations found. Asp, Glu, beta-Amglu and NMDA have a considerable flexibility and they can easily adopt the distance required. They leave a considerable population in conformations that present a COO-...COO- distance about 4A degrees. We propose that folded conformations are important for activity on QUIS-receptors, whereas extended conformations are the important on NMDA-receptors.
Ciuffo
G M
GM
Universidad Nacional de San Luis, Facultad de Química, Bioquímica y Farmacia, Argentina.
Estrada
M R
MR
Rodríguez
A M
AM
Jáuregui
E A
EA
D002490:Central Nervous System / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D007608:Kainic Acid / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D016202:N-Methylaspartate / Q000737:chemistry; D016318:Quisqualic Acid / Q000737:chemistry; D017981:Receptors, Neurotransmitter / Q000737:chemistry / Q000502:physiology*; D013329:Structure-Activity Relationship
D017981:Receptors, Neurotransmitter; D016202:N-Methylaspartate; D016318:Quisqualic Acid; D007608:Kainic Acid