title: Screening of 64 tryptamines at NMDA, 5-HT1A, and 5-HT2A receptors: a comparative binding and modeling study.
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 [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.
authors.affiliation: Center for Brain Research, Medical University of Vienna, A-1090 Spitalgasse 4, Austria. michael.berger@meduniwien.ac.at
authors.forename: M L
authors.initials: ML
authors.lastname: Berger
authors.forename: R
authors.initials: R
authors.lastname: Palangsuntikul
authors.forename: P
authors.initials: P
authors.lastname: Rebernik
authors.forename: P
authors.initials: P
authors.lastname: Wolschann
authors.forename: H
authors.initials: H
authors.lastname: Berner
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D008297:Male; D008566:Membranes / Q000378:metabolism; D008958:Models, Molecular; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014363:Tryptamines / Q000737:chemistry / Q000378:metabolism*
chemical_list: D044402:Receptor, Serotonin, 5-HT2A; D016194:Receptors, N-Methyl-D-Aspartate; D014363:Tryptamines; D044282:Receptor, Serotonin, 5-HT1A