Browsing by Author "Pessoa-Mahana, Hernan"

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    Motifs in Natural Products as Useful Scaffolds to Obtain Novel Benzo[d]imidazole-Based Cannabinoid Type 2 (CB2) Receptor Agonists
    (2023) Cho, Analia Young Hwa; Chung, Hery; Romero-Parra, Javier; Kumar, Poulami; Allara, Marco; Ligresti, Alessia; Gallardo-Garrido, Carlos; Pessoa-Mahana, Hernan; Faundez, Mario; Pessoa-Mahana, Carlos David
    The endocannabinoid system (ECS) constitutes a broad-spectrum modulator of homeostasis in mammals, providing therapeutic opportunities for several pathologies. Its two main receptors, cannabinoid type 1 (CB1) and type 2 (CB2) receptors, mediate anti-inflammatory responses; however, their differing patterns of expression make the development of CB2-selective ligands therapeutically more attractive. The benzo[d]imidazole ring is considered to be a privileged scaffold in drug discovery and has demonstrated its versatility in the development of molecules with varied pharmacologic properties. On the other hand, the main psychoactive component of Cannabis sativa, delta-9-tetrahydrocannabinol (THC), can be structurally described as an aliphatic terpenoid motif fused to an aromatic polyphenolic (resorcinol) structure. Inspired by the structure of this phytocannabinoid, we combined different natural product motifs with a benzo[d]imidazole scaffold to obtain a new library of compounds targeting the CB2 receptor. Here, we synthesized 26 new compounds, out of which 15 presented CB2 binding and 3 showed potent agonist activity. SAR analysis indicated that the presence of bulky aliphatic or aromatic natural product motifs at position 2 of the benzo[d]imidazoles ring linked by an electronegative atom is essential for receptor recognition, while substituents with moderate bulkiness at position 1 of the heterocyclic core also participate in receptor recognition. Compounds 5, 6, and 16 were further characterized through in vitro cAMP functional assay, showing potent EC50 values between 20 and 3 nM, and compound 6 presented a significant difference between the EC50 of pharmacologic activity (3.36 nM) and IC50 of toxicity (30-38 & mu;M).
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    Synthesis and Biological Screening of Novel Indolalkyl Arenes Targeting the Serotonine Transporter
    (2014) Ojeda-Gomez, Claudia; Pessoa-Mahana, Hernan; Iturriaga-Vasquez, Patricio; David Pessoa-Mahana, Carlos; Recabarren-Gajardo, Gonzalo; Mendez-Rojas, Claudio
    A series of functionalized indolylalkylarenes 3-16(a and b) were synthesized and their affinities for the serotonin transporter were investigated in vitro. Compounds 3-12(a and b) were obtained by nucleophilic substitution of 3-(1H-indol-3-yl)propyl-4-methylbenzenesulfonates 2(a and b) with a series of azaheterocycles. Compounds 14-16(a and b) were prepared in a two-step sequence by reaction of 3-(1H-indol-3-yl)-2-methylpropanal with substituted 1,2-phenylenediamines. Compounds 3b, 4b, and 5b showed good binding affinities (K-i=33.0, 48.0, and 17nM, respectively). The other synthesized compounds showed moderate or no affinity in the binding studies.
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    Synthesis, docking and pharmacological evaluation of novel homo- and hetero-bis 3-piperazinylpropylindole derivatives at SERT and 5-HT1A receptor
    (2013) Pessoa-Mahana, Hernan; Gonzalez-Lira, Christian; Fierro, Angelica; Zapata-Torres, Gerald; David Pessoa-Mahana, C.; Ortiz-Severin, Javiera; Iturriaga-Vasquez, Patricio; Reyes-Parada, Miguel; Silva-Matus, Paul; Saitz-Barria, Claudio; Araya-Maturana, Ramiro
    A series of 3-(3-(4-(3-(1H-indol-3-yl)propyl)piperazin-1-yl)propyl)-1H-indole derivatives (3a-d and 5a-f) as homo-and hetero-bis-ligands, were synthesized and evaluated for in vitro affinity at the serotonin transporter (SERT) and the 5-HT1A receptor. Compounds 5b and 5f showed nanomolar affinities for both targets. The experimental data were rationalized according to results obtained from docking experiments. These findings are in agreement with our proposal that bis-indole derivatives can bind both targets, and might serve as leads in the quest of ligands endowed with a dual mechanism of action. (C) 2013 Elsevier Ltd. All rights reserved.