A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site.

Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity and improve current medications by reducing off-target side effects. However, the lack of structural information on their binding mode impedes rational design.

Angiotensin-(1-5) is a Potent Endogenous Angiotensin AT -Receptor Agonist.

Background: The renin-angiotensin system involves many more enzymes, receptors and biologically active peptides than originally thought. With this study, we investigated whether angiotensin-(1-5) [Ang-(1-5)], a 5-amino acid fragment of angiotensin II, has biological activity, and through which receptor it elicits effects.

Methods: The effect of Ang-(1-5) (1µM) on nitric oxide release was measured by DAF-FM staining in human aortic endothelial cells (HAEC), or Chinese Hamster Ovary (CHO) cells stably transfected with the angiotensin AT -receptor (AT R) or the receptor Mas.

Structure of the dopamine D3 receptor bound to a bitopic agonist reveals a new specificity site in an expanded allosteric pocket.

Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity, driven by the binding of the secondary pharmacophore to non-conserved regions of the receptor. Although bitopic ligands have great potential to improve current medications by reducing off-target side effects, the lack of structural information on their binding mode impedes rational design.

Development of an automated, high-throughput assay to detect angiotensin AT-receptor agonistic compounds by nitric oxide measurements in vitro.

Angiotensin AT-receptor (ATR) agonists have shown a wide range of protective effects in many preclinical disease models. However, the availability of ATR-agonists is very limited due to the lack of high-throughput assays for ATR-agonist identification. Therefore, we aimed to design and validate an assay for high-throughput screening of ATR-agonist candidates.

Pharmacological and Physicochemical Properties Optimization for Dual-Target Dopamine D (DR) and μ-Opioid (MOR) Receptor Ligands as Potentially Safer Analgesics.

A new generation of dual-target μ opioid receptor (MOR) agonist/dopamine D receptor (DR) antagonist/partial agonists with optimized physicochemical properties was designed and synthesized. Combining in vitro cell-based on-target/off-target affinity screening, in silico computer-aided drug design, and BRET functional assays, we identified new structural scaffolds that achieved high affinity and agonist/antagonist potencies for MOR and DR, respectively, improving the dopamine receptor subtype selectivity (e.g.

Ligand and G-protein selectivity in the κ-opioid receptor.

The κ-opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorders. However, the development of KOR analgesics has been hindered by the associated hallucinogenic side effects. The initiation of KOR signalling requires the G-family proteins including the conventional (G, G, G, G and G) and nonconventional (G and G) subtypes.

Pharmacological Mechanism of the Non-hallucinogenic 5-HT Agonist Ariadne and Analogs.

Ariadne is a non-hallucinogenic analog in the phenylalkylamine chemical class of psychedelics that is closely related to an established synthetic hallucinogen, 2,5-dimethoxy-4-methyl-amphetamine (DOM), differing only by one methylene group in the α-position to the amine. Ariadne has been tested in humans including clinical trials at Bristol-Myers Company that indicate a lack of hallucinogenic effects and remarkable therapeutic effects, such as rapid remission of psychotic symptoms in schizophrenics, relaxation in catatonics, complete remission of symptoms in Parkinson's disease (PD), and improved cognition in geriatric subjects. Despite these provocative clinical results, the compound has been abandoned as a drug candidate and its molecular pharmacology remained unknown.

Electrochemical Studies of the Cycloaddition Activity of Bismuth(III) Acetylides Towards Organic Azides Under Copper(I)-Catalyzed Conditions.

Time-dependent monitoring of the reactive intermediates provides valuable information about the mechanism of a synthetic transformation. However, the process frequently involves intermediates with short lifetimes that significantly challenge the accessibility of the desired kinetic data. We report cyclic voltammetry (CV) and nuclear magnetic resonance (NMR) spectroscopy studies of the cycloaddition reaction of organobismuth(III) compounds with organic azides under the copper(I)-catalyzed conditions.

Dielectric Polymer Property Prediction Using Recurrent Neural Networks with Optimizations.

Despite the growing success of machine learning for predicting structure-property relationships in molecules and materials, such as predicting the dielectric properties of polymers, it is still in its infancy. We report on the effectiveness of solving structure-property relationships for a computer-generated database of dielectric polymers using recurrent neural network (RNN) models. The implementation of a series of optimization strategies was crucial to achieving high learning speeds and sufficient accuracy: (1) binary and nonbinary representations of SMILES (Simplified Molecular Input Line System) fingerprints and (2) backpropagation with affine transformation of the input sequence (ATransformedBP) and resilient backpropagation with initial weight update parameter optimizations (iRPROP optimized).