Towards rational design of cannabinoid receptor 1 (CB1) antagonists for peripheral selectivity

Fulp, Alan; Bortoff, Katherine; Zhang, Yanan; Seltzman, Herbert H.; Snyder, Rodney W.; Maitra, Rangan

doi:10.1016/j.bmcl.2011.08.032

Cited by 28 publications

(55 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Potent and selective compounds were progressed into an in vitro model of brain penetration in monolayers of MDCK-mdr1cells as described previously. 11b,13 Certain compounds were also characterized for metabolic stability in human hepatic microsomal fractions (S9). Finally, in vivo testing was conducted in Sprague–Dawley (SD) rats to measure CNS permeability of these compounds.…”

Section: Resultsmentioning

confidence: 99%

“…11b,13 MDCK-mdr1 cells obtained from Netherlands Cancer Institute were grown on Transwell type filters (Corning) for 4 days to confluence in DMEM/F12 media containing 10% fetal bovine serum and antibiotics as has been described previously. 13 Compounds were added to the apical side at a concentration of 10 μ M in a transport buffer comprising of 1× Hank’s balanced salt solution, 25 mM D-glucose and buffered with HEPES to pH 7.4.…”

Section: Methodsmentioning

confidence: 99%

“…First, charged compounds were produced based on the observation that such compounds cross the BBB only when transported by a specific transporter. 11 However, the compounds synthesized to date using this approach have low potency as reported in our previous publication. 11b The second strategy involved generation of compounds with high topological polar surface areas (TPSAs).…”

Section: Introductionmentioning

confidence: 92%

“…11 However, the compounds synthesized to date using this approach have low potency as reported in our previous publication. 11b The second strategy involved generation of compounds with high topological polar surface areas (TPSAs). Past studies indicate that compounds with high TPSA, usually >100, have lower permeability into the CNS.…”

Section: Introductionmentioning

confidence: 92%

See 3 more Smart Citations

Diphenyl Purine Derivatives as Peripherally Selective Cannabinoid Receptor 1 Antagonists

et al. 2012

Self Cite

View full text Add to dashboard Cite

Cannabinoid receptor 1 (CB1) antagonists are potentially useful for the treatment of several diseases. However, clinical development of several CB1 antagonists was halted due to central nervous system (CNS)-related side effects including depression and suicidal ideation in some users. Recently, studies have indicated that selective regulation of CB1 receptors in the periphery is a viable strategy for treating several important disorders. Past efforts to develop peripherally selective antagonists of CB1 have largely targeted rimonabant, an inverse agonist of CB1. Reported here are our efforts toward developing a peripherally selective CB1 antagonist based on the otenabant scaffold. Even though otenabant penetrates the CNS, it is unique among CB1 antagonists that have been clinically tested because it has properties that are normally associated with peripherally selective compounds. Our efforts have resulted in an orally absorbed compound that is a potent and selective CB1 antagonist with limited penetration into the CNS.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 92%

See 2 more Smart Citations

Diphenyl Purine Derivatives as Peripherally Selective Cannabinoid Receptor 1 Antagonists

et al. 2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…36,37 Compounds were added to the apical side at a concentration of 10 μ M in a transport buffer comprising 1× Hank’s balanced salt solution, 25 mM d -glucose, and buffered with HEPES to pH 7.4. Samples were incubated for 1 h at 37 °C and carefully collected from both the apical and basal side of the filters.…”

Section: Methodsmentioning

confidence: 99%

Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake

et al. 2018

Self Cite

View full text Add to dashboard Cite

The orphan G-protein-coupled receptor GPR88 is highly expressed in the striatum. Studies using GPR88 knockout mice have suggested that the receptor is implicated in alcohol seeking and drinking behaviors. To date, the biological effects of GPR88 activation are still unknown due to the lack of a potent and selective agonist appropriate for in vivo investigation. In this study, we report the discovery of the first potent, selective, and brain-penetrant GPR88 agonist RTI-13951-33 (6). RTI-13951-33 exhibited an EC50 of 25 nM in an in vitro cAMP functional assay and had no significant off-target activity at 38 GPCRs, ion channels, and neurotransmitter transporters that were tested. RTI-13951-33 displayed enhanced aqueous solubility compared to (1R,2R)-2-PCCA (2) and had favorable pharmacokinetic properties for behavioral assessment. Finally, RTI-13951-33 significantly reduced alcohol self-administration and alcohol intake in a dose-dependent manner without effects on locomotion and sucrose self-administration in rats when administered intraperitoneally.

show abstract

Molecular networks underlying cannabinoid signaling in skeletal muscle plasticity

Dalle

Schouten

Meeus

et al. 2022

Journal Cellular Physiology

View full text Add to dashboard Cite

The cannabinoid system is ubiquitously present and is classically considered to engage in neural and immunity processes. Yet, the role of the cannabinoid system in the whole body and tissue metabolism via central and peripheral mechanisms is increasingly recognized. The present review provides insights in (i) how cannabinoid signaling is regulated via receptor-independent and -dependent mechanisms and (ii) how these signaling cascades (might) affect skeletal muscle plasticity and physiology.Receptor-independent mechanisms include endocannabinoid metabolism to eicosanoids and the regulation of ion channels. Alternatively, endocannabinoids can act as ligands for different classic (cannabinoid receptor 1 [CB 1 ], CB 2 ) and/or alternative (e.g., TRPV1, GPR55) cannabinoid receptors with a unique affinity, specificity, and intracellular signaling cascade (often tissue-specific). Antagonism of CB 1 might hold clues to improve oxidative (mitochondrial) metabolism, insulin sensitivity, satellite cell growth, and muscle anabolism, whereas CB 2 agonism might be a promising way to stimulate muscle metabolism and muscle cell growth. Besides, CB 2 ameliorates muscle regeneration via macrophage polarization toward an anti-inflammatory phenotype, induction of MyoD and myogenin expression and antifibrotic mechanisms. Also TRPV1 and GPR55 contribute to the regulation of muscle growth and metabolism. Future studies should reveal how the cannabinoid system can be targeted to improve muscle quantity and/or quality in conditions such as ageing, disease, disuse, and metabolic dysregulation, taking into account challenges that are inherent to modulation of the cannabinoid system, such as central and peripheral side effects.

show abstract

Towards rational design of cannabinoid receptor 1 (CB1) antagonists for peripheral selectivity

Cited by 28 publications

References 22 publications

Diphenyl Purine Derivatives as Peripherally Selective Cannabinoid Receptor 1 Antagonists

Diphenyl Purine Derivatives as Peripherally Selective Cannabinoid Receptor 1 Antagonists

Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake

Molecular networks underlying cannabinoid signaling in skeletal muscle plasticity

Contact Info

Product

Resources

About