Screening of 64 Tryptamines at NMDA, 5-HT1A, and 5-HT2A Receptors: A Comparative Binding and Modeling Study

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Author list: Berger ML, Palangsuntikul R, Rebernik P, Wolschann P, Berner H

Publisher: Bentham Science Publishers

Publication year: 2012

Journal: Current Medicinal Chemistry (0929-8673)

Volume number: 19

Issue number: 18

Start page: 3044

End page: 3057

Number of pages: 14

ISSN: 0929-8673

eISSN: 1875-533X

URL: https://www.scopus.com/record/display.uri?eid=2-s2.0-84861852244&origin=resultslist&sort=plf-f&src=s&st1=Screening+of+64+Tryptamines+at+NMDA%2c+5-HT1A%2c+and+5-HT2A+Receptors%3a&sid=986f22327742012e99192b90e923d210&sot=b&sdt=b&sl=81&s=TITLE-ABS-KEY%28Screening+of+64+Tryptamines+at+NMDA%2c+5-HT1A%2c+and+5-HT2A+Receptors%3a%29&relpos=0&citeCnt=6&searchTerm=

Languages: English-Great Britain (EN-GB)

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Abstract

Tryptamine (T) and several T derivatives (Ts) inhibit in a voltage-dependent manner the NMDA receptor (NR). This effect is influenced by substituents at various positions, but has not yet been subjected to a detailed SAR study. Here, 64 Ts have been tested as inhibitors of [H-3]MK-801 binding to NRs on rat brain membranes. For comparison, they were also tested as inhibitors of [H-3]8-OH-DPAT binding to 5-HT1A and of [H-3] ketanserin binding to 5-HT2A receptors. Since most of these Ts have not been tested before at any of these receptors, we start with a review of the effects of Ts on 5-HT1A and 5-HT2A binding sites. NRs were inhibited with IC(50)s from 2 to 7 mu M by Ts with alkyl or halogen at positions 2, 5, and/or 7. Inhibition by some Ts was attenuated more than 10-fold by 30 mu M spermine. The most potent inhibitors at 5-HT1A receptors were 5-carboxamido-T (IC50 0.00015 mu M) and serotonin (0.0016 mu M), at 5-HT2A receptors 2-Me-4,7-Cl-2-T (1.2 mu M) and 2,7-Me-2-4-Cl-T (2.0 mu M). Fujita-Ban modified Free-Wilson analyses pointed to the individual significance of particular substituents. Also QSARs based on molecular operating environment descriptors resulted in sound correlations at all 4 targets. No similarities between the NR and 5-HT receptors could be found. At the NR, only L-Trp-NH2 bound 10 times better than at both 5-HT receptors studied. L-Trp-NH2 may be a structural lead to endogenous non-competitive NR antagonists.

Keywords

5-HT receptor, Free-Wilson Analysis, MOE descriptors, NMDA receptor, QSARs, Substituted tryptamines