Chemoenzymatic synthesis and cannabinoid activity of a new diazabicyclic amide of phenylacetylricinoleic acid.
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.
López-Ortíz
Manuel
M
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.
Herrera-Solís
Andrea
A
Luviano-Jardón
Axel
A
Reyes-Prieto
Nidia
N
Castillo
Ivan
I
Monsalvo
Ivan
I
Demare
Patricia
P
Méndez-Díaz
Mónica
M
Regla
Ignacio
I
Prospéro-García
Oscar
O
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
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