Synthesis and evaluation of 2-amido-3-carboxamide thiophene CB2 receptor agonists for pain management.

SAR studies on a series of thiophene amide derivatives provided CB(2) receptor agonists. The activity of the compounds was characterized by radioligand binding determination, multiple functional assays, ADME, and pharmacokinetic studies. A representative compound with selectivity for CB(2) over CB(1) effectively produced analgesia in behavioral models of neuropathic, inflammatory, and postsurgical pain. Control experiments using a CB(2) antagonist demonstrated the efficacy in the pain models resulted from CB(2) agonism.

Syntheses and structure-activity relationship (SAR) studies of 2,5-diazabicyclo[2.2.1]heptanes as novel alpha7 neuronal nicotinic receptor (NNR) ligands.

Biaryl substituted 2,5-diazabicyclo[2.2.1]heptanes have been synthesized and tested for their affinity toward alpha7 neuronal nicotinic receptors (NNRs). SAR studies established that 5-N-methyl substituent, heteroaryl linker and the nature of terminal aryl group are critical for the ligand to achieve potent alpha7 NNR agonist activity.

Characterization of a cannabinoid CB2 receptor-selective agonist, A-836339 [2,2,3,3-tetramethyl-cyclopropanecarboxylic acid [3-(2-methoxy-ethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]-amide], using in vitro pharmacological assays, in vivo pain models, and pharmacological magnetic resonance imaging.

Studies demonstrating the antihyperalgesic and antiallodynic effects of cannabinoid CB(2) receptor activation have been largely derived from the use of receptor-selective ligands. Here, we report the identification of A-836339 [2,2,3,3-tetramethyl-cyclopropanecarboxylic acid [3-(2-methoxy-ethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]-amide], a potent and selective CB(2) agonist as characterized in in vitro pharmacological assays and in in vivo models of pain and central nervous system (CNS) behavior models. In radioligand binding assays, A-836339 displays high affinities at CB(2) receptors and selectivity over CB(1) receptors in both human and rat. Likewise, A-836339 exhibits high potencies at CB(2) and selectivity over CB(1) receptors in recombinant fluorescence imaging plate reader and cyclase functional assays. In addition A-836339 exhibits a profile devoid of significant affinity at other G-protein-coupled receptors and ion channels. A-836339 was characterized extensively in various animal pain models. In the complete Freund's adjuvant model of inflammatory pain, A-836339 exhibits a potent CB(2) receptor-mediated antihyperalgesic effect that is independent of CB(1) or mu-opioid receptors. A-836339 has also demonstrated efficacies in the chronic constrain injury (CCI) model of neuropathic pain, skin incision, and capsaicin-induced secondary mechanical hyperalgesia models. Furthermore, no tolerance was developed in the CCI model after subchronic treatment with A-836339 for 5 days. In assessing CNS effects, A-836339 exhibited a CB(1) receptor-mediated decrease of spontaneous locomotor activities at a higher dose, a finding consistent with the CNS activation pattern observed by pharmacological magnetic resonance imaging. These data demonstrate that A-836339 is a useful tool for use of studying CB(2) receptor pharmacology and for investigation of the role of CB(2) receptor modulation for treatment of pain in preclinical animal models.

Structure-activity studies and analgesic efficacy of N-(3-pyridinyl)-bridged bicyclic diamines, exceptionally potent agonists at nicotinic acetylcholine receptors.

A series of exceptionally potent agonists at neuronal nicotinic acetylcholine receptors (nAChRs) has been investigated. Several N-(3-pyridinyl) derivatives of bridged bicyclic diamines exhibit double-digit-picomolar binding affinities for the alpha 4 beta 2 subtype, placing them with epibatidine among the most potent nAChR ligands described to date. Structure-activity studies have revealed that substitutions, particularly hydrophilic groups in the pyridine 5-position, differentially modulate the agonist activity at ganglionic vs central nAChR subtypes, so that improved subtype selectivity can be demonstrated in vitro. Analgesic efficacy has been achieved across a broad range of pain states, including rodent models of acute thermal nociception, persistent pain, and neuropathic allodynia. Unfortunately, the hydrophilic pyridine substituents that were shown to enhance agonist selectivity for central nAChRs in vitro tend to limit CNS penetration in vivo, so that analgesic efficacy with an improved therapeutic window was not realized with those compounds.