Skip to content

Thieno[3,2-b]- and Thieno[2,3-b]pyrrole Bioisosteric Analogues of the Hallucinogen and Serotonin Agonist N,N-Dimethyltryptamine

Joseph B. Blair, Danuta Marona‐lewicka, Arthi Kanthasamy, Virginia L. Lucaites, David L. Nelson, David E. Nichols

Journal of Medicinal Chemistry March 1, 1999 DOI: 10.1021/jm980692q (opens in new tab)

Relevant Not relevant

Study at a glance

AI-extracted from the abstract
Characteristics Experimental study Peer reviewed
Population LSD- and DOI-trained rats
Dose up to 50 micromol/kg
Measures drug discrimination paradigm, serotonin syndrome observation, receptor binding affinity assays
Topics Serotonin 5-MeO-DMT DMT
Keywords Tryptamines Hallucinogen Bioisostere Indole test 5-ht2 receptor Partial agonist Stereochemistry 5-HT Receptor Biological activity 5-ht1a receptor Pharmacology Chemical synthesis Biochemistry In vitro
Citations 63
Key findings Thienopyrrole bioisosteres of DMT lack LSD-like behavioral effects but act as potent 5-HT1A receptor agonists.

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-b]pyrrole (3b), thienopyrroles as potential bioisosteres of N,N-dimethyltryptamine (1a), 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 micromol/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)-1,3,4, 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.

Comparable studies

Other preclinical and animal studies on 5-MeO-DMT, most cited first.

Study Year Design Participants
Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. Human primary monocyte-derived dendritic cells 2014 In vitro study
Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats 2018 Experimental study
Hallucinogen-like actions of 5-methoxy-N,N-diisopropyltryptamine in mice and rats. Mice and rats 2006 Preclinical study
Agonist Properties of N,N-Dimethyltryptamine at Serotonin 5-HT2A and 5-HT2C Receptors Rats and transfected fibroblasts 1998 Experimental study
Subtypes of the 5-HT receptor mediating the behavioural responses to 5-methoxy-N,N-dimethyltryptamine in the rat Intact rats and rats depleted of monoamines with reserpine 1985 Experimental study

Citations in the library

Cited by 10

and 5 more in the library

Cites 3

Related reading

Explore topics

Serotonin 5-MeO-DMT DMT LSD