Chemoenzymatic synthesis and cannabinoid activity of a new diazabicyclic amide of phenylacetylricinoleic acid.
Manuel López-Ortíz, Andrea Herrera Solís, Axel Luviano-Jardón, Nidia Reyes-Prieto, Ivan Castillo, Ivan Monsalvo, Patricia Demare, Mónica Méndez-Díaz, Ignacio Regla, Oscar E. Prospéro García
Bioorganic & Medicinal Chemistry Letters June 1, 2010 DOI: 10.1016/j.bmcl.2010.04.074 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | PhAR-DBH-Me AM251 |
| Dose | 20 and 40 mg/kg PhAR-DBH-Me |
| Key points | PhAR-DBH-Me reduced core temperature and increased pain threshold at 20 and 40 mg/kg, and increased REM sleep at 20 mg/kg in rats; these effects were prevented or attenuated by the CB1 antagonist AM251. Place preference conditioning indicated the compound does not produce rewarding effects. The authors argue it possesses cannabinoid activity without reinforcement effects. |
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.