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NEUROPHARMACOLOGY

Synthesis and Characterization of NESS 0327: A Novel Putative Antagonist of the CB₁ Cannabinoid Receptor

Neuroscienze S.c.a r.l., Cagliari, Italy (S.R., G.M., S.T., P.C.); Department of Pharmacology, Chemistry, and Toxicology, University of Sassari, Sassari, Italy (G.A.P., J.-M.M.); "B.B. Brodie" Department of Neuroscience, University of Cagliari, Cagliari, Italy (P.S.); Section of Human Physiology and Nutrition, Department of Applied Sciences to Biosystems, University of Cagliari, Cagliari, Italy (R.V.); and C.N.R. Institute of Neurogenetics and Neuropharmacology and Neuroscienze S.c.a r.l, Selargius, Italy (L.P.)

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 (K_i = 350 ± 5 fM and 1.8 ± 0.075 nM, respectively) and a higher affinity for the CB₂ receptor (K_i = 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]GTPS) 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]GTPS 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 = 0.042 ± 0.01 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.

Address correspondence to: Dr. Luca Pani, Institute of Neurogenetic and Neuropharmacology, Via Boccaccio 8, 09047 Selargius, Italy. E-mail: l.pani{at}inn.cnr.it

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