Medicinal Chemistry, Pharmacology, and Potential Therapeutic Benefits of Cannabinoid CB₂ Receptor Agonists

Abstract

mino)-4-cyclopropyl-N-(tetrahydro-2Hpyran-4-yl)methyl)pyridine-3-carboxamide (2) 532 7.1.2. Preparation of 4-(6-((2R,5S)-2,5-Dimethylpyrrolidin-1-yl)pyridazin-3-yl)isoquinoline (6) 532 7.2. Sulfamoyl Benzamide 532 7.2.1. Preparation of N-[3,4-Dimethyl-5-(morpholin-4-ylsulfonyl)phenyl]-2,2-dimethyl butanamide (15) 532 7.3. Heterocyclic Ylidene 532 7.3.1. Preparation of (14E)-N-(3-tert-butyl-1-(Cyclopropylmethyl)-1,2-dihydro-2methylpyrazol-5-ylidene)-2-fluoro-3-(trifluoromethyl)benzamide (22) 533 7.4. Oxadiazole, α-Amidosulfone 533

Breaking barriers to novel analgesic drug development

“…The cannabinoid receptors, CB1 and CB2, have been intensively investigated as targets for potential pain therapeutics 85 . While CB1 receptor agonists produce severe psychotomimetic effects and have a large abuse potential, selective CB2 agonists produce analgesia in preclinical models without any major central side effects 85,86 .…”

“…While CB1 receptor agonists produce severe psychotomimetic effects and have a large abuse potential, selective CB2 agonists produce analgesia in preclinical models without any major central side effects 85,86 . While initially thought of as a peripherally restricted target, CB2 receptors are expressed in the CNS (Fig 2 and Fig 3), especially by spinal microglia and interneurons.…”

“…However, Arena Pharmaceuticals has published positive Phase Ib clinical trial results on its selective CB2 agonist, APD371 and is planning for Phase II trials in 2016–2017 91 . Several other candidates (Table 1), are also being evaluated in either Phase I or II trials 85,92–95 , the results of which are awaited.…”

“…Was the failure of the Pfizer compound a failure to access FAAH in the CNS? Certainly, cannabinoid agonists (CB1) have major actions in humans including claims of analgesia 85,86 . Clinical use of CB1 agonists or cannabis is complicated by the drug abuse liability from psychoactive effects, hence the theoretical attraction of elevating endocannabinoids.…”

Metal-free hydroarylation of the side chain carbon–carbon double bond of 5-(2-arylethenyl)-3-aryl-1,2,4-oxadiazoles in triflic acid

“…Oxadiazoles are an important class of heterocyclic compounds and great attention has been paid to their synthesis and to the studies of their chemical, physical and biological properties (see numerous reviews [1–8]). The oxadiazole ring represents an essential part of the pharmacophore in many drugs.…”