Design and synthesis of novel series of 5-HT6 receptor ligands having indole,a central aromatic core and 1-amino-4 methyl piperazine as a positive ionizable group

The exclusive distribution of 5-HT₆ receptor in the brain regions and high affinity for antipsychotic and antidepressant drugs makes 5-HT₆ receptor a promising target in treatment of CNS diseases. Based on a pharmacophore model reported in the literature, we designed and synthesized a novel series of 5-HT₆ receptor ligands having indole as a central aromatic core and 1-amino-4-methyl piperazine as positive ionizable group. Out of 32 compounds we have successfully identified 10 new compounds as 5-HT₆ receptor antagonists. The structure–activity relationship (SAR) studies have been carried out by mapping the compounds with the 3D QSAR model.     

Molecular docking and 3D QSAR studies on 1-amino-2-phenyl-4-(piperidin-1-yl)-butanes based on the structural modeling of human CCR5 receptor

In the present study, we have used an approach combining protein structure modeling, molecular dynamics (MD) simulation, automated docking, and 3D QSAR analyses to investigate the detailed interactions of CCR5 with their antagonists. Homology modeling and MD simulation were used to build the 3D model of CCR5 receptor based on the high-resolution X-ray structure of bovine rhodopsin. A series of 64 CCR5 antagonists, 1-amino-2-phenyl-4-(piperidin-1-yl)-butanes, were docked into the putative binding site of the 3D model of CCR5 using the docking method, and the probable interaction model between CCR5 and the antagonists were obtained. The predicted binding affinities of the antagonists to CCR5 correlate well with the antagonist activities, and the interaction model could be used to explain many mutagenesis results. All these indicate that the 3D model of antagonist-CCR5 interaction is reliable. Based on the binding conformations and their alignment inside the binding pocket of CCR5, three-dimensional structure-activity relationship (3D QSAR) analyses were performed on these antagonists using comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) methods. Both CoMFA and CoMSIA provide statistically valid models with good correlation and predictive power. The q(2)(r(cross)(2)) values are 0.568 and 0.587 for CoMFA and CoMSIA, respectively. The predictive ability of these models was validated by six compounds that were not included in the training set. Mapping these models back to the topology of the active site of CCR5 leads to a better understanding of antagonist-CCR5 interaction. These results suggest that the 3D model of CCR5 can be used in structure-based drug design and the 3D QSAR models provide clear guidelines and accurate activity predictions for novel antagonist design.     

Essential structure of orexin 1 receptor antagonist YNT-707, Part IV: The role of D-ring in 4,5-epoxymorphinan on the orexin 1 receptor antagonistic activity

The orexin 1 receptor (OX₁R) antagonists carrying a morphinan skeleton such as YNT-707 (2) and YNT-1310 (3) showed potent and extremely high selective antagonistic activity against OX₁R. In the course of our study of the essential structure of YNT-707 for high binding affinity against OX₁R, we prepared derivatives of 2 without the D- and 4,5-epoxy rings to clarify the roles of these structural determinants toward OX₁R antagonistic activity. The D- and 4,5-epoxy rings played important roles for the active orientation of the 17-sulfonamide and 6-amide side chains. Finally, we identified the simple structure required for selective OX₁R antagonistic activity in the complex morphinan skeleton, which is expected to be a useful scaffold for further design of OX₁R ligands.     

Novel ligands for the human histamine H1 receptor: synthesis, pharmacology, and comparative molecular field analysis studies of 2-dimethylamino-5-(6)-phenyl-1,2,3,4-tetrahydronaphthalenes

This paper reports the synthesis of a novel series of (+/-)-2-dimethylamino- 5- and 6-phenyl-1,2,3,4-tetrahydronaphthalene derivatives (5- and 6-APTs), and, corresponding affinity, functional activity, and, molecular modeling studies with regard to drug design targeting the human histamine H1 receptor. The 5-APTs have 2- to 4-fold higher H1 receptor affinity than the endogenous agonist histamine. The chemical nature of a meta-substituent on the 5-APT pendant phenyl moiety does not significantly affect H1 affinity. In contrast, analogous meta-substitution for the 6-APTs increases H1 affinity up to 100-fold. The new APTs do not activate H1 receptor-linked intracellular signaling and apparently are competitive H1 antagonists. A new model that establishes structural parameters for binding to the human H1 receptor by APTs and other ligands was developed using 3-D QSAR (CoMFA). The model predicts H1 ligand binding with a higher degree of external predictability compared to a previously reported model. The APTs also were examined for activity at human serotonin 5-HT2A and 5-HT2C receptors, which are phylogenetically closely related to the H1 receptor. 5-APT and m-Cl-6-APT were identified as novel agonists that selectively activate 5-HT2C receptors. It is concluded that the lipophilic (brain-penetrating) APT molecular scaffold may have pharmacotherapeutic potential in neuropsychiatric diseases.     

Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists

A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer.     

Thermodynamic assessment of the stability of thrombin receptor antagonistic peptides in hydrophobic environments

In this paper, a general procedure is described to determine thermodynamic parameters associated with the interaction of thrombin receptor antagonistic peptides (TRAPs) with immobilized nonpolar ligands. The results show that these interactions were associated with nonlinear van't Hoff dependencies over a wide temperature range. Moreover, changes in relevant thermodynamic parameters, namely the changes in Gibbs free energy of interaction, DeltaG(0)assoc, enthalpy of interaction, DeltaH(0)assoc, entropy of interaction, DeltaS(0)assoc, and heat capacity, DeltaC(0)p, have been related to the structural properties of these TRAP analogs. The implications of these investigations for the design of thrombin receptor agonists/antagonists with structures stabilized by intramolecular hydrophobic interactions are discussed.     

Synthesis and structure–activity relationship of novel diarylpyrazole imide analogues as CB1 cannabinoid receptor ligands

A myriad of research groups have been engaged in searching for novel CB1 receptor antagonists, since SR141716A (rimonabant), a CB1 receptor antagonist, was discovered for an obesity treatment. In this research, extended series, based on the 1,5-diarylpyrazole template of rimonabant, was synthesized and tested for CB1 receptor binding affinity. In the present study, N-piperidinylcarboxamide group of rimonabant was replaced with the corresponding sulfonamide, imide, N-methyl imide and methylenediamide, respectively. The SAR studies to optimize the CB1 binding affinity led to the potent imide derivatives. The in vivo efficacy test of a derivative (16f) gave a promising result for this novel scaffold. In order to explore physicochemical properties (hydrophobic, steric and electronic) of the representative imide derivatives responsible for their CB1 receptor binding affinity, quantitative structure activity relationship (QSAR) studies were performed. Hansch QSAR models, which were moderate in the explanation for SAR, were generated with hydrophobic, steric and electronic properties of substituents. Especially, the Taft Es-based parabolic model was obtained with the best correlation result (r² = 0.846).     

Structure and thermodynamic characterization of the EphB4/Ephrin-B2 antagonist peptide complex reveals the determinants for receptor specificity

The Eph receptor tyrosine kinases and their ligands, the ephrins, regulate numerous biological processes in developing and adult tissues and have been implicated in cancer progression and in pathological forms of angiogenesis. We report the crystal structure of the EphB4 receptor in complex with a highly specific antagonistic peptide at a resolution of 1.65 angstroms. The peptide is situated in a hydrophobic cleft of EphB4 corresponding to the cleft in EphB2 occupied by the ephrin-B2 G-H loop, consistent with its antagonistic properties. Structural analysis identifies several residues within the EphB4 binding cleft that likely determine the ligand specificity of this receptor, while isothermal titration calorimetry experiments with truncated forms of the peptide define the amino acid residues of the peptide that are critical for receptor binding. These studies reveal structural features that will aid drug discovery initiatives to develop EphB4 antagonists for therapeutic applications.     

3D-QSAR study indicates an enhancing effect of membrane ions on psychiatric drugs targeting serotonin receptor 5-HT1A

Antidepressants and antipsychotics are psychiatric agents used for the treatment of various types of psychiatric diseases. Although currently among the most commonly prescribed drugs, their effectiveness and adverse effects are the topic of many studies and controversial claims. Here we generate QSAR models based on compounds series including 20 drugs recommended for two critical psychiatric diseases: depression and schizophrenia and we use these QSAR models to predict the biological activity of these 20 antidepressants and antipsychotics. We establish the membrane ions' contributions (sodium, potassium, calcium and iron) mediated by water to the antagonism of these drugs at the 5-HT1A receptor. The reliability of our QSAR models in predicting compounds activity is indicated by significant values for cross-validated correlation q2 (0.60-0.76) and fitted correlation r2 (0.96-0.98) coefficients. Our results indicate that potassium, calcium and iron play a key role for the antagonistic activity of drugs at the 5-HT1A receptor. Moreover, based on the established QSAR equations, we analysed 24 new escitalopram derivatives as possibly improved antidepressants targeting the 5-HT1A receptor. We identified that the presence of methyl groups and hydrogen atoms improves antidepressant activity while the simultaneous presence of ethyl, propyl or halogens decreased drastically antidepressant activity at the 5-HT1A site.     

Novel non-steroidal/non-anilide type androgen antagonists: discovery of 4-substituted pyrrole-2-carboxamides as a new scaffold for androgen receptor ligands

We designed and synthesized novel pyrrole-2-carboxamide derivatives as androgen antagonists. Compounds 10 and 13 bearing benzylamine or aniline at the 4-position of the pyrrole ring showed moderate androgen antagonistic activity, and inhibited the androgen-dependent growth of Shionogi carcinoma cells (SC-3). Study of the structure-activity relationships of compound 13 led to a potent androgen antagonist 36, which has higher affinity than flutamide (4) for androgen nuclear receptor (AR). Thus, pyrrole-2-carboxamide is a new scaffold for developing AR antagonists.     

Ligands act as pharmacological chaperones and increase the efficiency of delta opioid receptor maturation

The endoplasmic reticulum (ER) is recognized as an important site for regulating cell surface expression of membrane proteins. We recently reported that only a fraction of newly synthesized delta opioid receptors could leave the ER and reach the cell surface, the rest being degraded by proteasomes. Here, we demonstrate that membrane-permeable opioid ligands facilitate maturation and ER export of the receptor, thus acting as pharmacological chaperones. We propose that these ligands stabilize the newly synthesized receptor in the native or intermediate state of its folding pathway, possibly by inducing stabilizing conformational constrains within the hydrophobic core of the protein. The receptor precursors that are retained in the ER thus represent fully competent folding intermediates that can be targets for pharmacological intervention aimed at regulating receptor expression and cellular responsiveness. The pharmacological chaperone action is independent of the intrinsic signaling efficacy of the ligand, since both agonists and antagonists were found to promote receptor maturation. This novel property of G protein-coupled receptor ligands may have important implications when considering their effects on cellular responsiveness during therapeutic treatments.     

Synthesis and structure-activity relationship of RXR antagonists based on the diazepinylbenzoic acid structure

Synthesis and structure-activity relationship of RXR antagonists employing a diazepinylbenzoic acid scaffold are described. Of those antagonists, sulfonamide derivatives (6v and 6w) reveal a high antagonistic activity and good pharmacokinetic properties.     

Tetrahydroquinoline-based selective estrogen receptor modulators (SERMs)

A new series of estrogen receptor ligands based on a 6-hydroxy-tetrahydroquinoline scaffold is described, in addition to their binding affinity and functional activity in MCF-7 cells. Several 1,2-disubstituted tetrahydroquinolines bearing a basic side chain were shown to be high affinity ligands and antagonists in the MCF-7 proliferation assay. Compounds lacking the basic side chain were agonists in the MCF-7 assay.     

QSAR modeling,pharmacophore-based virtual screening,and ensemble docking insights into predicting potential epigallocatechin gallate (EGCG) analogs against epidermal growth factor receptor

Epigallocatechin gallate (EGCG) is a major polyphenols of green tea may have the possibility to inhibit epidermal growth factor receptor (EGFR) activity and lead to reduce non-small cell lung cancer (NSCLC) progression. However, EGCG has some toxic features; moreover, there is a lack of explorations into the molecular interaction mechanisms of EGCG and the EGFR. In this examination, integration of quantitative structure–activity relationship (QSAR) modeling, pharmacophore-based virtual screening, and ensemble docking approaches were used to predict potential novel EGCG analogs as effective EGFR inhibitors. QSAR modeling of logP and logS predictions and toxicity endpoint investigation for a set of 82 compounds were shown good predictive ability and robustness from the applicability domain and confusion matrix elucidations. Virtual screening and docking studies revealed that seven high potential EGCG analogs as strong EGFR binders. Molecular interactions interpretations indicated some insights into the structural features of ligands that efficiently interfere with mutation possible residues (Gly⁷¹⁹ and Thr⁷⁹⁰) of the EGFR. The hydrogen bonds, hydrophobic interactions, atomic π-cation interactions and salt bridges of ligands are contributing additional stability to receptor structure, which can lead to blocking the intracellular protein-tyrosine kinase activity, including EGFR associated pathways activation in NSCLC. Therefore, this can characterize as a block-cluster mechanism between EGCG analogs and EGFR complexes. In silico anti-EGFR and anticancer activity predictions suggested that, ligands could act as promising pharmacological, anticancer, and drug-like templates of EGFR towards moderating the NSCLC progressions. These results and provided pinpoints could be beneficial to recognize probable therapeutic targets for NSCLC therapy.     

Synthesis and structure-affinity relationships of 4-(5-Aryl-1,2,3,6-tetrahydropyridino)pyrimidine derivatives as corticotropin-releasing factor(1) receptor antagonists

Recently, various non-peptide corticotropin-releasing factor(1) (CRF(1)) receptor antagonists have been reported. Structure-affinity relationships (SARs) of non-peptide CRF(1) antagonists suggest that such antagonists can be constructed of three units: a hydrophobic unit (Up-Area), a proton accepting unit (Central-Area), and an aromatic unit (Down-Area). We previously presented 4-aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives including potent CRF receptor ligands 1a and 1b and proposed that the 4-aryl-1,2,3,6-tetrahydropyridino moiety might be useful as a substituent in the Up-Area. Our interest shifted to 5-aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives 2, among which compound 2m (CRA0165) had highest affinity for CRF(1) receptors (IC(50)=11nM). We report here the design, synthesis and SARs of derivatives 2.     

Identification of a new small molecule chemotype of Melanin Concentrating Hormone Receptor-1 antagonists using pharmacophore-based virtual screening

MCH receptor is a G protein-coupled receptor with two subtypes R1 and R2. Many studies have demonstrated the role of MCH-R1 in feeding and energy homeostasis. It has been proven that oral administration of small molecule MCH-R1 antagonists significantly reduces food intake and causes a dose-dependent weight loss. In this study, two ligand-based pharmacophores were developed and validated based on recently published MCH-R1 antagonists with diverse structures. Successful pharmacophores had one hydrogen bond acceptor, one positive ionizable, one ring aromatic and two or three hydrophobic groups. These 3D-QSAR models were used for virtual screening of the ZINC chemical database resulting in the identification of nine compounds with more than 50% displacement of radiolabeled MCH at a 20 μM concentration. Moreover, four of these compounds showed antagonistic activities in Aequorin functional assay, including MH-3 which is the first MCH-R1 antagonist based on a diazaspiro[4.5]decane scaffold. The most active compounds were also docked into our previously published MCH-R1 homology model to gain insights into their binding determinants. These compounds could represent a viable starting scaffold for the design of potent MCH-R1 antagonists with improved pharmacokinetic properties as an effective treatment for obesity.     

QSAR study on the affinity of some arylpiperazines towards the 5-HT1A/alpha1-adrenergic receptor using the E-state index

QSAR models represent the relationship of biological activity with either physicochemical parameters or structural indices. QSAR study was performed on some arylpiperazines as 5-HT(1A)/alpha(1)-adrenergic receptor antagonists using E-state indices to identify the pharmacophoric requirements. It was found that some of the atoms played important roles to both activities and some played important role in selectivity of compound to the 5-HT(1A) antagonistic activity. The presence of COONHPr group at the ortho-position of the phenyl ring might be disadvantageous and Br at meta-position might be conducive to the activity. COOPr at the ortho-position might be disfavored the adrenergic alpha(1)-antagonistic activity, thus increase the selectivity.     

Computational studies of the binding modes of A<Subscript>2A</Subscript> adenosine receptor antagonists

A molecular docking study was performed on several structurally diverse A(2A) AR antagonists, including xanthines, and non-xanthine type antagonists to investigate their binding modes with A(2A) adenosine receptor (AR), one of the four subtypes of AR, which is currently of great interest as a target for therapeutic intervention, in particular for Parkinson's disease. The high-affinity binding site was found to be a hydrophobic pocket with the involvement of hydrogen bonding interactions as well as pi-pi stacking interactions with the ligands. The detailed binding modes for both xanthine and non-xanthine type A(2A) antagonists were compared and the essential features were extracted and converted to database searchable queries for virtual screening study of novel A(2A) AR antagonists. Findings from this study are helpful for elucidating the binding pattern of A(2A) AR antagonists and for the design of novel active ligands.     

2D-QSAR and 3D-QSAR/CoMFA analyses of the N-terminal substituted anthranilic acid based CCK1 receptor antagonists: ‘Hic Rhodus,hic saltus’

A research is presented on quantitative structure–activity relationship (QSAR) studies on the more recent class of non-peptidic CCK₁ receptor antagonists. Our results suggest that the balance of hydrophobicity and volume dependent polarizability term plays a key role in the antagonism of CCK₁ receptor. The size of the substitution of ligands at particular position which induce steric fit is crucial as well as their hydrophobic contribution. Indicator variables were used after the best model was found to account for the usual structural features.The CoMFA results show a good variance explanation and the best self-predictivity is slightly lower than 60% with both leave-one-out and random-group methods. The CoMFA molecular fields showed the importance of steric hindrance of the substituent. From the GRIND models it can be deduced that the shape differences of the molecules are secondary in the regulation of the activity, or better, that their polar substituents are capable of occupying the same zones of the space in the most of the cases.