Synthesis, cannabinoid receptor affinity, molecular modeling studies and in vivo pharmacological evaluation of new substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides. 2. Effect of the 3-carboxamide substituent on the affinity and selectivity profile.

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Silvestri R, Ligresti A, La Regina G, Piscitelli F, Gatti V, Brizzi A, Pasquini S, Lavecchia A, Allara M, Fantini N, Carai MA, Novellino E, Colombo G, Di Marzo V, Corelli F

Bioorg Med Chem. 2009 Aug 1;17(15):5549-64. doi: 10.1016/j.bmc.2009.06.027. Epub 2009 Jun 21.

PubMed ID

19595596 [ View in PubMed

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Abstract

New substituted 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized by replacing the 2,4-dichlorobenzyl and cyclohexyl moieties at the 3-carboxamide nitrogen of the previously reported CB(1) receptor antagonists/inverse agonists 4 and 5. Several ligands showed potent affinity for the hCB(1) receptor, with K(i) concentrations comparable to the reference compounds 1, 4 and 5, and exhibited CB(1) selectivity comparable to 1 and 2. Docking experiments and molecular dynamics (MD) simulations explained the potent hCB(1) binding affinity of compounds 31 and 37. According to our previous studies, 31 and 37 formed a H-bond with K3.28(192), which accounted for the high affinity for the receptor inactive state and the inverse agonist activity. The finding of inhibition of food intake following their acute administration to rats, supported the concept that the CB(1) selective compounds 4 and 52 act as antagonists/inverse agonists.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Rimonabant	Cannabinoid receptor 1	Ki (nM)	12	N/A	N/A	Details