A number of studies indicate that cannabinoids can reduce intraocular pressure (IOP) both in animals and humans, suggesting a putative efficacy of these compounds in the treatment of glaucoma. Among the cannabinoid derivatives encompassed by Patent US 7,485,730 assigned to PharmaNess Scarl, different compounds characterized by low or absent permeability toward blood brain barrier evidenced agonism activity on both CB1 and CB2 sub-type cannabinoid receptors. In this study we report the synthesis and pharmacological profile of a new compounds claimed by the above mentioned Patent: N-menthyl-6-methyl-1-(4''-methylbenzyl)-1,4dihydrothieno[2',3':4,5]cyclopenta[1,2-c]pyrazol-3-carboxamide (NESS040C5). The affinity towards both CB1 and CB2 receptors was determined through radioreceptor binding assays according to the procedure reported by Ruiu et al. in J.P.E.T., 2003, 306, 363−370, while the activity at those receptors was evaluated using an in vitro cell culture model. To evaluate the pharmacological application of the compound in glaucoma treatment, a validated animal model based on the IOP determination in aged glaucomatous DBA/2J mice was adopted. NESS040C5 showed high affinity at both CB1 and CB2 receptors, which were positively modulated suggesting an agonistic activity of the derivative. In addiction, the compound reduced IOP in DBA/2J glaucomatous mice suggesting a potential efficacy of NESS040C5 in the treatment of glaucoma.
Receptorial and pharmacological characterization of the new cannabinoid agonist NESS040C5
DESSI', CHRISTIAN;FALZOI, MATTEO;
2009-01-01
Abstract
A number of studies indicate that cannabinoids can reduce intraocular pressure (IOP) both in animals and humans, suggesting a putative efficacy of these compounds in the treatment of glaucoma. Among the cannabinoid derivatives encompassed by Patent US 7,485,730 assigned to PharmaNess Scarl, different compounds characterized by low or absent permeability toward blood brain barrier evidenced agonism activity on both CB1 and CB2 sub-type cannabinoid receptors. In this study we report the synthesis and pharmacological profile of a new compounds claimed by the above mentioned Patent: N-menthyl-6-methyl-1-(4''-methylbenzyl)-1,4dihydrothieno[2',3':4,5]cyclopenta[1,2-c]pyrazol-3-carboxamide (NESS040C5). The affinity towards both CB1 and CB2 receptors was determined through radioreceptor binding assays according to the procedure reported by Ruiu et al. in J.P.E.T., 2003, 306, 363−370, while the activity at those receptors was evaluated using an in vitro cell culture model. To evaluate the pharmacological application of the compound in glaucoma treatment, a validated animal model based on the IOP determination in aged glaucomatous DBA/2J mice was adopted. NESS040C5 showed high affinity at both CB1 and CB2 receptors, which were positively modulated suggesting an agonistic activity of the derivative. In addiction, the compound reduced IOP in DBA/2J glaucomatous mice suggesting a potential efficacy of NESS040C5 in the treatment of glaucoma.
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