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Synthesis and characterization of NESS 0327: a novel putative antagonist of the CB1 cannabinoid receptor

Ruiu, Stefania and Pinna, Gérard Aimé and Marchese, Giorgio and Mussinu, Jean-Mario and Saba, Pierluigi and Tambaro, Simone and Casti, Paola and Vargiu, Romina and Pani, Luca (2003) Synthesis and characterization of NESS 0327: a novel putative antagonist of the CB1 cannabinoid receptor. Journal of Pharmacology and Experimental Therapeutics, Vol. 306 (1), p. 363-370. eISSN 1521-0103. Article.

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DOI: 10.1124/jpet.103.049924


The compound N-piperidinyl-[8-chloro-1-(2,4-dichlorophenyl)- 1,4,5,6-tetrahydrobenzo [6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide] (NESS 0327) was synthesized and evaluated for binding affinity toward cannabinoid CB1 and CB2 receptor. NESS 0327 exhibited a stronger selectivity for CB1 receptor compared with N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl- 1H-pyrazole-3-carboxamide (SR 141716A), showing a much higher affinity for CB1 receptor (Ki = 350 ± 5 fM and 1.8 ± 0.075 nM, respectively) and a higher affinity for the CB2 receptor (Ki = 21 ± 0.5 nM and 514 ± 30 nM, respectively). Affinity ratios demonstrated that NESS 0327 was more than 60,000-fold selective for the CB1 receptor, whereas SR 141716A only 285-fold. NESS 0327 alone did not produce concentration-dependent stimulation of guanosine 5'-O-(3-[35S]thio)-triphosphate ([35S]GTPγS) binding in rat cerebella membranes. Conversely, NESS 0327 antagonized [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrolol [1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate] (WIN 55,212-2)-stimulated [35S]GTPγS binding. In functional assay, NESS 0327 antagonized the inhibitory effects of WIN 55,212-2 on electrically evoked contractions in mouse isolated vas deferens preparations with pA2 value of 12.46 ± 0.23. In vivo studies indicated that NESS 0327 antagonized the antinociceptive effect produced by WIN 55,212-2 (2 mg/kg s.c.) in both tail-flick (ID50 = 0.0420 ± 01 mg/kg i.p.) and hot-plate test (ID50 = 0.018 ± 0.006 mg/kg i.p.). These results indicated that NESS 0327 is a novel cannabinoid antagonist with high selectivity for the cannabinoid CB1 receptor.

Item Type:Article
ID Code:399
Uncontrolled Keywords:NESS 0327, cannabinoid antagonist, CB1 receptor, piperidines, pyrazoles, chemical synthesis, pharmacology
Subjects:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Divisions:001 Università di Sassari > 01 Dipartimenti > Farmaco, chimico, tossicologico
Publisher:American Society for Pharmacology and Experimental Therapeutics
Deposited On:18 Aug 2009 10:02

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