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Vascular pharmacology of a novel cannabinoid-like compound, 3-(5-dimethylcarbamoyl-pent-1-enyl)-N-(2-hydroxy-1-methyl-ethyl)benzamide (VSN16) in the rat.
Br J Pharmacol. 2007 Nov; 152(5):751-64.BJ

Abstract

BACKGROUND AND PURPOSE

A putative novel cannabinoid receptor mediates vasorelaxation to anandamide and abnormal-cannabidiol and is blocked by O-1918 and by high concentrations of rimonabant. This study investigates VSN16, a novel water-soluble agonist, as a vasorelaxant potentially acting at non-CB1, non-CB2 cannabinoid receptors in the vasculature.

EXPERIMENTAL APPROACH

VSN16 and some analogues were synthesized and assayed for vasodilator activity in the rat third generation mesenteric artery using wire myography. Also carried out with VSN16 were haemodynamic studies in conscious rats and binding studies to CB1 receptors of rat cerebellum.

KEY RESULTS

VSN16 relaxed mesenteric arteries in an endothelium-dependent manner. The vasorelaxation was antagonized by high concentrations of the classical cannabinoid antagonists, rimonabant and AM 251, as well as by O-1918, an antagonist at the abnormal-cannabidiol receptor but not at CB1 or CB2 receptors. It did not affect [3H]CP55,940 binding to CB1 receptors in rat cerebellum. The vasorelaxation was not pertussis toxin-sensitive but was reduced by inhibition of nitric oxide synthesis, Ca(2+)-sensitive K+ channels (KCa) and TRPV1 receptors. In conscious rats VSN16 transiently increased blood pressure and caused a longer-lasting increase in mesenteric vascular conductance. Structure-activity studies on vasorelaxation showed a stringent interaction with the target receptor.

CONCLUSIONS AND IMPLICATIONS

VSN16 is an agonist at a novel cannabinoid receptor of the vasculature. It acts on the endothelium to release nitric oxide and activate KCa and TRPV1. As it is water-soluble it might be useful in bringing about peripheral cannabinoid-like effects without accompanying central or severe cardiovascular responses.

Authors+Show Affiliations

Department of Pharmacology, University of Cambridge, Cambridge, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17891160

Citation

Hoi, P M., et al. "Vascular Pharmacology of a Novel Cannabinoid-like Compound, 3-(5-dimethylcarbamoyl-pent-1-enyl)-N-(2-hydroxy-1-methyl-ethyl)benzamide (VSN16) in the Rat." British Journal of Pharmacology, vol. 152, no. 5, 2007, pp. 751-64.
Hoi PM, Visintin C, Okuyama M, et al. Vascular pharmacology of a novel cannabinoid-like compound, 3-(5-dimethylcarbamoyl-pent-1-enyl)-N-(2-hydroxy-1-methyl-ethyl)benzamide (VSN16) in the rat. Br J Pharmacol. 2007;152(5):751-64.
Hoi, P. M., Visintin, C., Okuyama, M., Gardiner, S. M., Kaup, S. S., Bennett, T., Baker, D., Selwood, D. L., & Hiley, C. R. (2007). Vascular pharmacology of a novel cannabinoid-like compound, 3-(5-dimethylcarbamoyl-pent-1-enyl)-N-(2-hydroxy-1-methyl-ethyl)benzamide (VSN16) in the rat. British Journal of Pharmacology, 152(5), 751-64.
Hoi PM, et al. Vascular Pharmacology of a Novel Cannabinoid-like Compound, 3-(5-dimethylcarbamoyl-pent-1-enyl)-N-(2-hydroxy-1-methyl-ethyl)benzamide (VSN16) in the Rat. Br J Pharmacol. 2007;152(5):751-64. PubMed PMID: 17891160.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Vascular pharmacology of a novel cannabinoid-like compound, 3-(5-dimethylcarbamoyl-pent-1-enyl)-N-(2-hydroxy-1-methyl-ethyl)benzamide (VSN16) in the rat. AU - Hoi,P M, AU - Visintin,C, AU - Okuyama,M, AU - Gardiner,S M, AU - Kaup,S S, AU - Bennett,T, AU - Baker,D, AU - Selwood,D L, AU - Hiley,C R, Y1 - 2007/09/24/ PY - 2007/9/25/pubmed PY - 2008/2/26/medline PY - 2007/9/25/entrez SP - 751 EP - 64 JF - British journal of pharmacology JO - Br J Pharmacol VL - 152 IS - 5 N2 - BACKGROUND AND PURPOSE: A putative novel cannabinoid receptor mediates vasorelaxation to anandamide and abnormal-cannabidiol and is blocked by O-1918 and by high concentrations of rimonabant. This study investigates VSN16, a novel water-soluble agonist, as a vasorelaxant potentially acting at non-CB1, non-CB2 cannabinoid receptors in the vasculature. EXPERIMENTAL APPROACH: VSN16 and some analogues were synthesized and assayed for vasodilator activity in the rat third generation mesenteric artery using wire myography. Also carried out with VSN16 were haemodynamic studies in conscious rats and binding studies to CB1 receptors of rat cerebellum. KEY RESULTS: VSN16 relaxed mesenteric arteries in an endothelium-dependent manner. The vasorelaxation was antagonized by high concentrations of the classical cannabinoid antagonists, rimonabant and AM 251, as well as by O-1918, an antagonist at the abnormal-cannabidiol receptor but not at CB1 or CB2 receptors. It did not affect [3H]CP55,940 binding to CB1 receptors in rat cerebellum. The vasorelaxation was not pertussis toxin-sensitive but was reduced by inhibition of nitric oxide synthesis, Ca(2+)-sensitive K+ channels (KCa) and TRPV1 receptors. In conscious rats VSN16 transiently increased blood pressure and caused a longer-lasting increase in mesenteric vascular conductance. Structure-activity studies on vasorelaxation showed a stringent interaction with the target receptor. CONCLUSIONS AND IMPLICATIONS: VSN16 is an agonist at a novel cannabinoid receptor of the vasculature. It acts on the endothelium to release nitric oxide and activate KCa and TRPV1. As it is water-soluble it might be useful in bringing about peripheral cannabinoid-like effects without accompanying central or severe cardiovascular responses. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/17891160/Vascular_pharmacology_of_a_novel_cannabinoid_like_compound_3__5_dimethylcarbamoyl_pent_1_enyl__N__2_hydroxy_1_methyl_ethyl_benzamide__VSN16__in_the_rat_ L2 - https://doi.org/10.1038/sj.bjp.0707470 DB - PRIME DP - Unbound Medicine ER -