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Purinergic receptor P2X3 has been linked to analgesia in a number of pre-clinical models of pain, and is expressed in the human pain perception pathway. Only few P2X3-selective antagonists have been reported to date. This Letter describes the SAR and in vivo analgesic profile of a novel scaffold of selective P2X3 antagonists., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

An oral, peripherally restricted CB1/CB2 agonist could provide an interesting approach to treat chronic pain by harnessing the analgesic properties of cannabinoids but without the well-known central side effects. γ-Carbolines are a novel class of potent mixed CB1/CB2 agonists characterized by attractive physicochemical properties including high aqueous solubility. Optimization of the series has led to the discovery of 29, which has oral activity in a rat inflammatory pain model and limited brain exposure at analgesic doses, consistent with a lower risk of CNS-mediated tolerability issues., (Copyright © 2012. Published by Elsevier Ltd.)

A series of 1-aminotetralin scaffolds was synthesized via metal-catalyzed ring-opening reactions of heterobicyclic alkenes. Small libraries of amides and amines were made using the amino group of each scaffold as a handle. Screening of these libraries against human opioid receptors led to the identification of (S)-(S)-5.2a as a high-affinity selective mu ligand (IC(50)mu=5 nM, kappa=707 nM, delta=3,795 nM) displaying mu-agonist/antagonist properties due to its partial agonism (EC(50)=2.6 microM; E(max)=18%).

The preparation and evaluation of a novel class of CB2 agonists based on a benzimidazole moiety are reported. They showed binding affinities up to 1nM towards the CB2 receptor with partial to full agonist potencies. They also demonstrated good to excellent selectivity (>1000-fold) over the CB1 receptor.

A series of Dmt-Tic analogues with substitution on the Tic aromatic ring has been synthesized and evaluated for opioid receptor affinity and activation. Incorporation of large hydrophobic groups at position 7 of Tic did not greatly alter the delta opioid receptor binding affinities of the dipeptides whereas substitution at position 6 substantially diminished their affinity. These modified Dmt-Tic peptides showed binding affinities as low as 2.5 nM with up to 500-fold selectivity for the delta versus mu opioid receptor and proved to be delta receptor antagonists.