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Blair, J.B., Marona-lewicka, D., Kanthasamy, A., Lucaites, V.L., Nelson, D.L., and Nichols, D.E..
“Thieno [3,2-b]- and Thieno[2,3-b] pyrrole Bioisosteric Analogues of the Hallucinogen and Serotonin Agonist N,N-Dimethyltryptamine”.
Journal of Medicinal Chemistry. 1999;42(6):1106-11.
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Abstract
The synthesis and biological activity of 6-[2-(N,N-dimethylamino)ethyl]-4H-thieno[3 2-b]pyrrole (3a) and 4-[2-(N,N-dimethylamino)ethyl]-6H-thieno[2,3-6]pyrrole (3b), thienopyrroles as potential bioisosteres of N,N-dimethyltryptamine (la), are reported. Hallucinogen-like activity was evaluated in the two-lever drug discrimination paradigm using LSD- and DOI-trained rats. Neither 3a nor 3b substituted for LSD or DOI up to doses of 50 µmol/kg. By comparison, 1a fully substituted in LSD-trained rats. However, 3a and 3b fully substituted for the 5-HT1A agonist LY293284 ((-)-(4R)-6-acetyl-4-(di-n-propylamino)-l,3,4,5-tetrahydrobenz[c,d]indole). Both 3a and 3b induced a brief "serotonin syndrome" and salivation, an indication of 5-HT1A receptor activation. At the cloned human 5-HT2A receptor 3b had about twice the affinity of 3a. At the cloned human 5-HT2B and 5-HT2C receptors, however, 3a had about twice the affinity of 3b. Therefore, thiophene lacks equivalence as a replacement for the phenyl ring in the indole nucleus of tryptamines that bind to 5-HT2 receptor subtypes and possess LSD-like behavioral
effects. Whereas both of the thienopyrroles had lower affinity than the corresponding 1a at 5-HT2 receptors, 3a and 3b had significantly greater affinity than 1a at the 5-HT1A receptor. Thus, thienopyrrole does appear to serve as a potent bioisostere for the indole nucleus in compounds that bind to the serotonin 5-HT1A. receptor. These differences in biological activity suggest that serotonin receptor isoforms are very sensitive to subtle changes in the electronic character of the aromatic systems of indole compounds
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