Future Therapeutic Potential of Synthetic Cannabinoids and Endocannabinoid System Modulators

Davis, Mellar P.

doi:10.1007/978-3-030-89918-9_3

Cited by 1 publication

(1 citation statement)

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“…CB1 and CB2 receptors share 44% amino acid homology and differ in their localization in the human body [ 3 ]. The CB1 receptor is one of the most abundant GPCRs in the brain, and this distribution correlates with its role in controlling motor function, cognition and memory, and pain relief [ 4 ]. The CB2 receptor is predominantly expressed in immune cells and moderately expressed in other peripheral tissues, including the cardiovascular system, gastrointestinal (GI) tract, liver, adipose tissue, bone, and reproductive system [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Systematic Modification of the Substitution Pattern of the 7-Hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide Scaffold Enabled the Discovery of New Ligands with High Affinity and Selectivity for the Cannabinoid Type 2 Receptor

Mugnaini,

Kostrzewa,

Casini

et al. 2023

Molecules

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Selective ligands of the CB2 receptor are receiving considerable attention due to their potential as therapeutic agents for a variety of diseases. Recently, 7-hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide derivatives were shown to act at the CB2 receptor either as agonists or as inverse agonists/antagonists in vitro and to have anti-osteoarthritic activity in vivo. In this article, we report the synthesis, pharmacological profile, and molecular modeling of a series of twenty-three new 7-hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamides with the aim of further developing this new class of selective CB2 ligands. In addition to these compounds, seven other analogs that had been previously synthesized were included in this study to better define the structure–activity relationship (SAR). Ten of the new compounds studied were found to be potent and selective ligands of the CB2 receptor, with Ki values ranging from 48.46 to 0.45 nM and CB1/CB2 selectivity indices (SI) ranging from >206 to >4739. In particular, compounds 54 and 55 were found to be high-affinity CB2 inverse agonists that were not active at all at the CB1 receptor, whereas 57 acted as an agonist. The functional activity profile of the compounds within this structural class depends mainly on the substitution pattern of the pyrazole ring.

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Section: Introductionmentioning

confidence: 99%