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Compounds with activity at serotonin (5‐hydroxytryptamine) 5‐HT2 and α1 adrenergic receptors have potential for the treatment of central nervous system disorders, drug addiction or overdose. Isolaureline, dicentrine and glaucine enantiomers were synthesized, and their in vitro functional activities at human 5‐HT2 and adrenergic α1 receptor subtypes were evaluated. The enantiomers of isolaureline and dicentrine acted as antagonists at 5‐HT2 and α1 receptors with (R)‐isolaureline showing the greatest potency (pKb = 8.14 at the 5‐HT2C receptor). Both (R)‐ and (S)‐glaucine also antagonized α1 receptors, but they behaved very differently to the other compounds at 5‐HT2 receptors: (S)‐glaucine acted as a partial agonist at all three 5‐HT2 receptor subtypes, whereas (R)‐glaucine appeared to act as a positive allosteric modulator at the 5‐HT2A receptor. The (R)‐ and (S)‐enantiomers of isolaureline and dicentrine act as antagonists at 5‐HT2 and α1 receptors with (R)‐isolaureline showing the greatest potency (pKb = 8.14 at the 5‐HT2C receptor). Both (R)‐ and (S)‐glaucine also antagonize α1 receptors, but the two enantiomers behave very differently at 5‐HT2 receptors: (S)‐glaucine acts as a partial agonist at all three 5‐HT2 receptor subtypes, whereas (R)‐glaucine appears to act as a positive allosteric modulator at the 5‐HT2A receptor. [ABSTRACT FROM AUTHOR]

Highlights: [•] A homology model of the human M1 mAChR was generated. [•] Modification and refinement by IFD gave two activated structures. [•] IFD-refined structures efficiently differentiated agonists from decoys. [•] The activated structures also gave good agonist/antagonist selectivity. [•] Structural differences suggest changes that occur upon ligand binding. [ABSTRACT FROM AUTHOR]

Background: The vast diversity of peptide sequences may hinder the effectiveness of screening for potential peptide therapeutics as if searching for a needle in a haystack. This study aims to develop a new self-evolving peptide algorithm (SEPA), for easy virtual screening of small linear peptides (three to six amino acids) as potential therapeutic agents with the collaborative use of freely available software that can be run on any operating system equipped with a Bash scripting terminal. Mitogen-inducible Gene 6 (Mig6) protein, a cytoplasmic protein responsible for inhibition and regulation of epidermal growth factor receptor tyrosine kinase, was used to demonstrate the algorithm., Objective: The objective is to propose a new method to discover potential novel peptide inhibitors via an automated peptide generation, docking and post-docking analysis algorithm that ranks short peptides by using essential hydrogen bond interaction between peptides and the target receptor., Methods: A library of dockable dipeptides were first created using PyMOL, Open Babel and AutoDockTools, and docked into the target receptor using AutoDock Vina, automatically via a Bash script. The docked peptides were then ranked by hydrogen bond interaction-based thorough interaction analysis, where the top-ranked peptides were then elongated, docked, and ranked again. The process repeats until the user-defined peptide length is achieved., Results: In the tested example, SEPA bash script was able to identify the tripeptide YYH ranked within top 20 based on the essential hydrogen bond interaction towards the essential amino acid residue ASP837 in the EGFR-TK receptor., Conclusion: SEPA could be an alternative approach for the virtual screening of peptide sequences against drug targets., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Compounds with activity at serotonin (5-hydroxytryptamine) 5-HT 2 and α 1 adrenergic receptors have potential for the treatment of central nervous system disorders, drug addiction or overdose. Isolaureline, dicentrine and glaucine enantiomers were synthesized, and their in vitro functional activities at human 5-HT 2 and adrenergic α 1 receptor subtypes were evaluated. The enantiomers of isolaureline and dicentrine acted as antagonists at 5-HT 2 and α 1 receptors with (R)-isolaureline showing the greatest potency (pK b  = 8.14 at the 5-HT 2C receptor). Both (R)- and (S)-glaucine also antagonized α 1 receptors, but they behaved very differently to the other compounds at 5-HT 2 receptors: (S)-glaucine acted as a partial agonist at all three 5-HT 2 receptor subtypes, whereas (R)-glaucine appeared to act as a positive allosteric modulator at the 5-HT 2A receptor., (© 2018 John Wiley & Sons A/S.)

[This corrects the article DOI: 10.1039/C7MD00629B.].

In this study, the ( S )-enantiomers of the aporphine alkaloids, nuciferine and roemerine, were prepared via a synthetic route involving catalytic asymmetric hydrogenation and both stereoisomers were evaluated in vitro for functional activity at human 5-HT 2 and adrenergic α 1 receptor subtypes using a transforming growth factor-α shedding assay. Both enantiomers of each of the compounds were found to act as antagonists at 5-HT 2 and α 1 receptors. ( R )-roemerine was the most potent compound at 5-HT 2A and 5-HT 2C receptors (p K b = 7.8-7.9) with good selectivity compared to ( S )-roemerine at these two receptors and compared to its activity at 5-HT 2B , α 1A , α 1B and α 1D receptors.

Muscarinic acetylcholine receptor-active compounds have potential for the treatment of Alzheimer's disease. In this study, a series of natural and synthetic flavones and flavonols was assayed in vitro for their ability to inhibit radioligand binding at human cloned M1 muscarinic receptors. Several compounds were found to possess competitive binding affinity (Ki=40-110 µM), comparable to that of acetylcholine (Ki=59 µM). Despite the fact that these compounds lack a positively-charged ammonium group under physiological conditions, molecular modelling studies suggested that they bind to the orthosteric site of the receptor, mainly through non-polar interactions.