C. David Pessoa-Mahana

A synthetic overview of new molecules with 5-HT1A binding affinities.

The present review discusses the synthetic strategies of new ligands exhibiting mainly 5-HT(1A)binding affinities. Specifically we focused our attention in the synthesis of compounds structurally related to arylpiperazine, 2-aminotetralin, and benzopyran derivatives.

Computational modeling study of functional microdomains in cannabinoid receptor type 1

The seven transmembrane helices (TMH) G-protein-coupled receptors (GPCRs) constitute one of the largest superfamily of signaling proteins found in mammals. Some of its members, in which the cannabinoid (CB) receptors are included, stand out because their functional states can be modulated by a broad spectrum of effector molecules. The relative ligand promiscuity exhibited by these receptors could be related with particular attributes conferred by their molecular architecture and represents a motivating issue to be explored. In this regard, this study represents an effort to investigate the cannabinoid receptor type 1 (CB1) ligand recognition plasticity, using comparative modeling, molecular dynamics (MD) simulations and docking. Our results suggest that a cooperative set of subtle structural rearrangements within the TMHs provide to the CB1 protein the plasticity to reach alternate configurations. These changes include the relaxation of intramolecular constraints, the rotations, translations and kinks of the majority of TMHs and the reorganization of the ligand binding cavities.

Synthesis of 4‐Arylpiperazine Derivatives of Moclobemide: Potential Antidepressants with a Dual Mode of Action

Abstract We report here the synthesis of substituted 4‐chloro‐N‐[3‐oxo‐3‐(4‐aryl‐1‐piperazinyl)‐propyl] benzamides (5–9), as potential new antidepressants, incorporating in a single molecule structural moieties related to a dual pharmacological profile: MAO‐A inhibitor and 5‐HT1A receptor affinity.

Solvent-free microwave synthesis of 3-(4-benzo〔b〕-thiophene-2-carbonyl)-1-piperazinyl-1-benzo〔b〕thiophen-2-yl-1-propanones: new hetero bis-ligands with potential 5-HT1A serotonergic activity

- A novel series of2-benzothiophenealkylpiperazine derivatives 11(a-d) with potential affinity at 5-HT 1A serotonin receptors have been synthesized via solvent-free, microwave-promoted Michael addition of benzo[b]thiophene piperazine derivatives 6(a-c) to substituted benzo[b]thiophen-2-yl propenones 10(b,c).

Combined CoMFA and CoMSIA 3D-QSAR study of benzimidazole and benzothiophene derivatives with selective affinity for the CB2 cannabinoid receptor

ABSTRACT The preceding years have brought an exponential increase in our understanding of the endocannabinoid system (ECS), including the knowledge of CB1 and CB2 cannabinoid receptors, endocannabinoids, and the enzymes that synthesize and degrade endocannabinoids. Among these ECS components CB2 receptors have been the subject of considerable attention, primarily due to their promising therapeutic potential to treat numerous pathologies while avoiding the adverse psychotropic effects that can accompany CB1 receptor–based therapies. Recently, our research group has reported a new series of non‐cytotoxic benzo[d]imidazoles and benzo[b]thiophenes displaying high CB2/CB1 selectivity index. In order to investigate the structural requirements for CB2 ligands and to derive a predictive model that can be used for the design of novel selective CB2 ligands, a three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) study was performed on the above mentioned chemical series employing comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques. The CoMFA and CoMSIA models displayed high external predictability (rpred2 0.919 and 0.908) and good statistical robustness. Valuable information regarding the steric, electrostatic and hydrophobic properties of the molecules was obtained, and several modifications around both heterocycles were evaluated with the aim to generate new promising series of benzo[d]imidazoles and benzo[b]thiophenes derivatives displaying high CB2 selectivity and low toxicity. Graphical abstract Figure. No Caption available.

Synthesis, docking studies and biological evaluation of benzo[b]thiophen-2-yl-3-(4-arylpiperazin-1-yl)-propan-1-one derivatives on 5-HT1A serotonin receptors.

A series of novel benzo[b]thiophen-2-yl-3-(4-arylpiperazin-1-yl)-propan-1-one derivatives 6a–f, 7a–f and their corresponding alcohols 8a–f were synthesized and evaluated for their affinity towards 5-HT1A receptors. The influence of arylpiperazine moiety and benzo[b]thiophene ring substitutions on binding affinity was studied. The most promising analogue, 1-(benzo[b]thiophen-2-yl)-3-(4-(pyridin-2-yl)piperazin-1-yl)propan-1-one (7e) displayed micromolar affinity (Ki = 2.30 μM) toward 5-HT1A sites. Docking studies shed light on the relevant electrostatic interactions which could explain the observed affinity for this compound.

Evaluation of the Membrane Permeability (PAMPA and Skin) of Benzimidazoles with Potential Cannabinoid Activity and their Relation with the Biopharmaceutics Classification System (BCS)

The permeability of five benzimidazole derivates with potential cannabinoid activity was determined in two models of membranes, parallel artificial membrane permeability assay (PAMPA) and skin, in order to study the relationship of the physicochemical properties of the molecules and characteristics of the membranes with the permeability defined by the Biopharmaceutics Classification System. It was established that the PAMPA intestinal absorption method is a good predictor for classifying these molecules as very permeable, independent of their thermodynamic solubility, if and only if these have a Log Poct value <3.0. In contrast, transdermal permeability is conditioned on the solubility of the molecule so that it can only serve as a model for classifying the permeability of molecules that possess high solubility (class I: high solubility, high permeability; class III: high solubility, low permeability).

1-BENZOYL-2-(2-NITROPHENYL)-1H-BENZIMIDAZOLE DERIVATIVES: A NOVEL APPROACH TO THE DEVELOPMENT OF NEW HIV-1 REVERSE TRANSCRIPTASE INHIBITORS

A novel approach to the development of a new class of HIV-1 RT inhibitors is reported. The 1-benzoyl-2-aryl-1H-benzimidazole series was designed as a combination of two previously reported active scaffolds, the benzimidazole and benzoyl moieties. The active compounds of the series effectively blocked the reverse transcription in the micromolar range in an in vitro assay containing the wild-type enzyme. We have demonstrated that the 2-nitrophenyl C-2 substituent is an important structural feature for the desired biological activity in this series. Molecular docking experiments suggest that the active compounds adopt a butterflylike conformation within the binding pocket of the enzyme, with the benzoyl moiety located in an extended hydrophobic region defined mainly by Tyrl 81, Tyrl 88, and Trp229

Synthesis of Benzo[b]thiophene Carboxamides Connected to 4‐Arylpiperazines through a Benzylic Spacer: Potential Ligands with 5‐HT1A Binding Affinity

Abstract New benzothiophene arylpiperazine derivatives 8 (a–f) were synthesized as potential serotoninergic agents with 5‐HT1A receptor affinity. Preparation of the derivatives was performed by treating N‐[2‐(chloromethyl)phenyl]‐4,7‐dimethoxybenzo[b]thiophene‐2‐carboxamide (7) with a series of substituted 4‐arylpiperazines.

A Facile Approach for New Dibenzo [b,f][1,5] Diazocinones

Abstract The synthesis of new eight‐membered cycle dibenzo[b,f][1,5]‐diazocine‐6‐(5H)‐one derivatives 11, 12 was developed. The key step in this synthesis was the intramolecular cyclization of the amino aldehyde precursors 9,10 obtained by a selective reduction of the nitro benzamides 7, 8.