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 [3H]MK-801 binding to NRs on rat brain membranes. For comparison, they were also tested as inhibitors of [3H]8-OHDPAT
binding to 5-HT1A and of [3H]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 IC50s from 2 to 7
μM 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 μM spermine.
The most potent inhibitors at 5-HT1A receptors were 5-carboxamido-T (IC50 0.00015 μM) and serotonin (0.0016 μM), at 5-HT2A receptors
2-Me-4,7-Cl2-T (1.2 μM) and 2,7-Me2-4-Cl-T (2.0 μM). 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: Substituted tryptamines, NMDA receptor, 5-HT receptor, QSARs, Free-Wilson Analysis, MOE descriptors, T derivatives (Ts), ketanserin binding, alkyl or halogen, endogenous
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