Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects.

Positive allosteric modulators (PAMs) of the mu-opioid receptor (MOR) have been hypothesized as potentially safer analgesics than traditional opioid drugs. This is based on the idea that PAMs will promote the action of endogenous opioid peptides while preserving their temporal and spatial release patterns and so have an improved therapeutic index. However, this hypothesis has never been tested.

Discovery and SAR of aryl hydroxy pyrimidinones as potent small molecule agonists of the GPCR APJ.

This article describes the discovery of aryl hydroxy pyrimidinones and the medicinal chemistry efforts to optimize this chemotype for potent APJ agonism. APJ is a G-protein coupled receptor whose natural agonist peptide, apelin, displays hemodynamic improvement in the cardiac function of heart failure patients. A high throughput screen was undertaken to identify small molecule hits that could be optimized to mimic the apelin in vitro response.

2,6-Bis(benzimidazol-2-yl)pyridine complexes of group 14 elements.

Treatment of MCl (M = Ge or Sn) with 2,6-bis(benzimidazol-2-yl)pyridine (G-BZIMPY, G = NBn, N(3,5-CF)Bn, NAllyl and O) yielded the self-ionization products [G-BZIMPYMCl][MCl] (1-6) in high yields (75-98%). Reduction reactions are examined and the nickel complexes 8 and 9 ([(NBn-BZIMPY)Ni][MCl]) are isolated from the reaction of Ni(COD) with 1 and 2 respectively. [NBn-BZIMPYSnCl][SnCl] shows a significantly stronger MLCT band in the UV-vis absorption spectrum than its germanium counterparts, with germanium complexes exhibiting negative solvatochromism that is not observed in tin complexes.

Halogen and Sulfur Oxidation of Germanium and Tin Dications.

Herein we present the oxidation of base-stabilized tetrel dications [LM][OTf] [L = BIMEt = tris(1-ethyl-benzoimidazol-2-ylmethyl)amine and M = Ge, Sn] with PCl, SeCl, Br, and I to access dicationic dihalides [LMX][OTf]. The addition of oxygen-rich donor molecules (picoline N-oxide, OPEt) to dications [LM][OTf] yielded donor-acceptor complexes bearing a tetrel(II) dication adjacent to a pnictogen(V) moiety. The addition of elemental sulfur to [LGe][OTf] yielded [(LGeS)][OTf] containing a dimeric tetracation.

Identification and biochemical analyses of selective CB agonists.

Cannabinoid CB and CB receptors are activated by Δ-tetrahydrocannabinol, a psychoactive component of marijuana. The cannabinoid CB receptor is primarily located in the brain and is responsible for the psychoactive side effects, whereas the cannabinoid CB receptor is located in immune cells and is an attractive target for immune-related maladies. We identify small molecules that selectively bind to the cannabinoid CB receptor and can be further developed into therapeutics.