Glutamate is one of the most important excitatory neurotransmitters in the central nervous systems and plays significant role in the pathophysiology of numerous neurological and psychiatric disorders [1,2]. Indole derivatives with aromatic substituent at C2 make new class of the non-competitive, partial GluR5/GluR6 antagonists. Between them 1-ethyl-2-(methoxyphenyl)-3-methyl-5-methoxy-indole was found to be the most potent (EC₅₀ = 0.2 mm) in contrary to the derivative having rigidly bonded C2 pharmacophoric aromatic substituent, which show no activity.

Basic structural and conformational information obtained from X-ray investigations were used to explanation the dramatic changes in the glutamate receptor GluR5/6 affinity with the changes of the spatial location of the C2 substituent. The molecular modeling studies using molecular mechanic method and MNDO-AM1 approximation were undertaken to investigate the conformational preferences of searched derivatives.

[1] S. Bleich, K. Romer, J. Wiltfang, J. Kornhuber, International Journal of Geriatric Psychiatry, 2003, 18 (Suppl. 1), 33.

[2] M. Nedergaard, T. Takano, A. J. Hansen, Nature Reviews Neuroscience, 2002, 9, 748.

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