title: Chemoenzymatic synthesis and cannabinoid activity of a new diazabicyclic amide of phenylacetylricinoleic acid.
abstract: Endocannabinoids (eCBs) are endogenous neuromodulators of synaptic transmission. Their dysfunction may cause debilitating disorders of diverse clinical manifestation. For example, drug addiction, lack of sex desire, eating disorders, such as anorexia or bulimia and dyssomnias. eCBs also participate in the regulation of core temperature and pain perception. In this context, it is important to recognize the utility of cannabinoid receptor 1 (CB1R) agonists, natural as Delta(9)-tetrahydrocannabinol (THC) or synthetic as Nabilone as useful drugs to alleviate this kind of patients' suffering. Therefore, we have developed a new drug, (R,Z)-18-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-18-oxooctadec-9-en-7-yl phenylacetate (PhAR-DBH-Me), that appears to bind and activate the CB1R. This diazabicyclic amide was synthesized from phenylacetylricinoleic acid and (1S,4S)-2,5-diazabicyclo[2.2.1]heptane. To test its cannabinergic properties we evaluated its effects on core temperature, pain perception, and the sleep-waking cycle of rats. Results indicate that 20 and 40mg/kg of PhAR-DBH-Me readily reduced core temperature and increased pain perception threshold. In addition, 20mg/kg increased REM sleep in otherwise normal rats. All these effects were prevented or attenuated by AM251, a CB1R antagonist. Place preference conditioning studies indicated that this molecule does not produce rewarding effects. These results strongly support that PhAR-DBH-Me possesses cannabinoid activity without the reinforcement effects.
authors.affiliation: Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Batalla del 5 de Mayo y Fuerte de Loreto, Iztapalapa 09230, Mexico, D.F., Mexico.
authors.forename: Manuel
authors.initials: M
authors.lastname: López-Ortíz
authors.forename: Andrea
authors.initials: A
authors.lastname: Herrera-Solís
authors.forename: Axel
authors.initials: A
authors.lastname: Luviano-Jardón
authors.forename: Nidia
authors.initials: N
authors.lastname: Reyes-Prieto
authors.forename: Ivan
authors.initials: I
authors.lastname: Castillo
authors.forename: Ivan
authors.initials: I
authors.lastname: Monsalvo
authors.forename: Patricia
authors.initials: P
authors.lastname: Demare
authors.forename: Mónica
authors.initials: M
authors.lastname: Méndez-Díaz
authors.forename: Ignacio
authors.initials: I
authors.lastname: Regla
authors.forename: Oscar
authors.initials: O
authors.lastname: Prospéro-García
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D001372:Aza Compounds / Q000737:chemistry*; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D002186:Cannabinoids / Q000138:chemical synthesis* / Q000494:pharmacology*; D009829:Oleic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D012890:Sleep / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects
chemical_list: C551308:18-(5-methyl-2,5-diazabicyclo(2.2.1)heptan-2-yl)-18-oxooctadec-9-en-7-yl phenylacetate; D000577:Amides; D001372:Aza Compounds; D053961:Azabicyclo Compounds; D001643:Bridged Bicyclo Compounds; D002186:Cannabinoids; D009829:Oleic Acids; D043884:Receptor, Cannabinoid, CB1