Synthesis and Biological Evaluation of Novel 5,8‐Disubstituted‐2‐methyl‐2,3,4,5‐tetrahydro‐1H‐pyrido[4,3‐b] indoles as 5‐HT₆ and H₁ Receptors Antagonists

Abstract

Synthesis, biological evaluation, and structure-activity relationships (SAR) for a series of novel gamma-carboline analogues of Dimebon are described. Among the studied compounds, tetrahydro-gamma-carboline 5b (2,8-dimethyl-5-[cis-2-pyridin-3-ylvinyl]-2,3,4,5-tetrahydro-carboline) has been identified as the most potent small molecule antagonist, in particular against histamine H(1) and serotonin 5-HT(6) receptors (IC(50) < 0.45 microM and IC(50) = 0.73 microM, respectively). A thorough comparative SAR study performed for the tested compounds has revealed significant correlations between the nature of side substituents and the related antagonistic activity.

γ-Carbolines and their hydrogenated derivatives 3.* Hydrogenated derivatives of γ-carbolines: chemical and biological poperties (Review)

“…There are data on the occurrence of similar transformations for bromoethynylbenzene [2]. Under analogous conditions with bromoazines in the presence of N,N'-dimethylethylenediamine it was possible to obtain 25-56% yields of the corresponding derivatives containing an azine fragment at position 5 of the γ-carboline skeleton [37].…”

“…Tetrahydro-γ-carbolines add to aryl-and pyridylalkynes with good yields under the conditions of phasetransfer catalysis with the formation of a mixture of the (Z)-and (E)-isomers of the 5-vinyl derivatives 10; they can be reduced to the corresponding 5-(2-arylethyl)tetrahydro-γ-carbolines 11, which cannot be obtained by addition to styrenes [37,43]. Sulfonyl halides react readily with N(5)-unsubstituted γ-carbolines in the presence of NaH in DMF with the formation of the corresponding N-sulfonyl derivatives [2,44].…”

“…An example of the ethynylation of a tetrahydro-γ-carboline derivative at the N(5) atom with 3-(bromoethynyl)pyridine in the presence of copper sulfate is known [37]. There are data on the occurrence of similar transformations for bromoethynylbenzene [2].…”

“…This makes it possible to regard the compounds as potential products for the treatment of neurodegenerative illnesses. Such compounds include, for example, 5-(2-hetarylethyl) [28], 5-(2-pyridylvinyl) [37], and 8-sulfonyl [44] derivatives of tetrahydro-γ-carbolines. The drug Dimebon 2 [28,130], which will be discussed in greater detail below, is regarded as an antagonist of serotonin 5-HT 6 -receptors.…”

Syntheses and radioligand activities of dimebon analogs

“…The newly synthesized THPIs also contained an analogous picoline group but it was bonded to THPI directly (IV) or through methylene (IX), cis-or trans-vinyl (XI, XII), acetylene (XIV), or 1,3-propylene (XXI) linkers. [13,14] for arylation of indole and THPI using 3-iodo-6-methylpyridine (III) (Scheme 1) [15].…”