Peripherally Selective Cannabinoid 1 Receptor (CB1R) Agonists for the Treatment of Neuropathic Pain

Abstract

Alleviation of neuropathic pain by cannabinoids is limited by their central nervous system (CNS) side effects. Indole and indene compounds were engineered for high hCB1R affinity, peripheral selectivity, metabolic stability, and in vivo efficacy. An epithelial cell line assay identified candidates with <1% blood-brain barrier penetration for testing in a rat neuropathy induced by unilateral sciatic nerve entrapment (SNE). The SNE-induced mechanical allodynia was reversibly suppressed, partially or completely, after intraperitoneal or oral administration of several indenes. At doses that relieve neuropathy symptoms, the indenes completely lacked, while the brainpermeant CB1R agonist HU-210 (1) exhibited strong CNS side effects, in catalepsy, hypothermia, and motor incoordination assays. Pharmacokinetic findings of ~0.001 cerebrospinal fluid:plasma ratio further supported limited CNS penetration. Pretreatment with selective CB1R or CB2R blockers suggested mainly CB1R contribution to an indene's antiallodynic effects. Therefore, this class of CB1R agonists holds promise as a viable treatment for neuropathic pain. Graphical abstract*

Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists

“…In the current study, we found that notable synergy occurred in the SNI neuropathic pain model. Traumatic nerve injury-induced increases in pro-inflammatory mediators and glial activation is likely due to spontaneous activity of sensory neurons in the CNS, an effect that can be alleviated by targeting peripheral endocannabinoids (Fox et al, 2001; Mitrirattanakul et al, 2006; Seltzman et al, 2016) and/or CB2 activation (Watkins et al, 2007). Repeated treatment with the selective CB2 agonists JWH133 (Elmes et al, 2004) or NESS400 (Luongo et al, 2010) reduced hypertrophic microglia in a significant manner, while importantly, sparing microglial cell number in rodent models of SNL/SNI.…”

Palladium‐Catalyzed Tunable Carbonylative Synthesis of Enones and Benzofulvenes

“…[18][19][20][21] Indenes have also been widely used in materials [22][23][24][25][26] as well as ligands for metal complexes. It is generallyk nown that indene derivative, including methyleneindene (benzofulvene),i so ne of the most important carbocycles in organic chemistry.T his framework presents frequently in many natural products and biologically active compounds.…”

“…It is generallyk nown that indene derivative, including methyleneindene (benzofulvene),i so ne of the most important carbocycles in organic chemistry.T his framework presents frequently in many natural products and biologically active compounds. [18][19][20][21] Indenes have also been widely used in materials [22][23][24][25][26] as well as ligands for metal complexes. [27][28][29] Severals trategies have been developed for the synthesis of 1H-indenes and benzofulvenes.…”

Targeting Peripherally Restricted Cannabinoid Receptor 1, Cannabinoid Receptor 2, and Endocannabinoid-Degrading Enzymes for the Treatment of Neuropathic Pain Including Neuropathic Orofacial Pain

“…One strategy is to target CB1 receptors localized in the peripheral tissues [61][62][63][64]. CB1 agonists with limited or no ability to pass the blood-brain barrier have been developed for this purpose and tested in preclinical animal models [63,64]. Another strategy is to selectively target CB2 receptors because they are predominantly expressed outside of the brain.…”