G protein‐coupled receptor binding and pharmacological evaluation of indole‐derived thiourea compounds

Abstract

Four 2-(1H-indol-3-yl)ethylthiourea derivatives were prepared by condensation of 2-(1H-indol-3-yl)ethanamine with the corresponding aryl/alkylisothiocyanates in a medium-polarity solvent. Their structures were confirmed by spectral techniques, and the molecular structure of 3 was determined by X-ray crystal analysis. For all derivatives, the binding affinities at the 5-HT 2A and 5-HT 2C receptors, as well as their functional activities at the 5-HT 1A and D 2 receptors, were determined. The arylthioureas 1 and 4 were the most active at the 5-HT 1A receptor, showing, at the same time, significant selectivity over the studied 5-HT 2 and D 2 receptor subtypes.The compounds were tested for their pharmacological activities within the central nervous system in relevant mouse models. The involvement of the serotonergic system in the activity of 1 and 4 was indicated. The antinociceptive action of 4 was linked to its anti-inflammatory activity. K E Y W O R D Sdopamine receptors, inverse agonists, serotonin antagonism, substituent effect

Cytotoxicity Evaluation of Novel bis(2-aminoethyl)amine Derivatives

“…The strong dependence between cytotoxic activity and the presence of electronegative elements on the phenyl moiety or an alkyl linker at the thiourea part, was proven by our team previously [ 5 , 6 , 7 , 8 , 9 , 12 , 13 , 14 , 15 , 16 , 17 ].…”

“…From the synthetic point of view, this motif was used to obtain mono-, di-, and cyclic substituted compounds [ 5 , 6 , 7 , 8 , 9 ]. Most of them were built on a heterocyclic scaffold, which is sometimes a complex one [ 10 , 11 , 12 , 13 ]. Most of these compounds showed significant biological activity.…”

Identification of a Potent and Selective 5-HT1A Receptor Agonist with In Vitro and In Vivo Antinociceptive Activity

“…The synthesis of the titled compounds was performed as previously reported, using (S)-3-chloro-propan-1,2-diol or (R)-3chloropropan-1,2-diol to prepare (S)-5 and (R)-5, respectively. 1 (6). 8 (440 mg, 1.40 mmol, 1 equiv) was solubilized in a 1:1 mixture of TFA:DCM at 0 °C.…”

“…The titled compound was obtained as a pale yellow liquid (290 mg, 97% yield), which was pure enough to be used in the next step without further purification. 1 H NMR (400 MHz,Chloroform-d) δ 1.71 (br s, 2H), 2.99 (t, J = 5.0 Hz, 2H), 3.99 (t, J = 5.0 Hz, 2H), 6 Synthesis of 2-(2-(1-Methyl-1H-imidazol-5-yl)phenoxy)ethan-1amine (7). The N-Boc cleavage of 9 was performed as reported above for the synthesis of 6.…”

“…5-HT 1A Rs are highly expressed throughout the pain neuroaxis where they exert a clear antinociceptive action by inhibiting the transmission of nociceptive signals . Indeed, full and partial 5-HT 1A R agonists have shown to be effective in the treatment of pain. − In addition, the use of 5-HT 1A agonists in combination with opioids could be particularly advantageous, since they are able to reduce addiction, by decreasing the reward effects of opioids and to revert opioid-induced respiratory depression …”