Inhibition of fatty acid amidohydrolase (FAAH), the enzyme responsible for the selective in vivo degradation of the endocannabinoid anandamide, elicits CB1 receptor-mediated anxiolytic, analgesic and cardiovascular depressor effects, without inducing behavioral effects predictive of addictive potential. In collaboration with Dr. Alex Makriyannis, we have developed and patented a novel FAAH inhibitor, AM3506, and are currently characterizing its pharmacological/therapeutic profile. Last year we reported that AM3506 normalizes the elevated blood pressure and inappropriately increased cardiac contractility of both anesthetized and conscious spontaneously hypertensive rats (SHR) via a centrally mediated reduction in sympathetic tone, without affecting these parameters in normotensive animals. Additionally, AM3506 does not induce metabolic side effects including hyperglycemia/glucose intolerance, which are seen with other FAAH inhibitors, such as URB597, or in FAAH-/- mice, and are due to inhibition of FAH in the liver and the consequent increase in hepatic anndamide levels that result in activation of hepatic CB1 receptors. The unique lack of such side effects with AM3506 is due to its very rapid metablism by the liver, resulting in ts inabiliity to block FAAH in the liver. This unique pharmacologic profile suggests that AM3506 may have theraputic potential in hypertension. These results have been published in Chemistry &Biology. Endocannabinoids acting via CB1 receptors in the amygdala have been implicated in the extinction of aversive memories (Nature 418:530, 2002), a process that plays a central role in post-traumatic stress syndrome (PTSD). Because AM3506 causes marked elevation of anandamide levels in the brain, Dr. Andrew Holmes group, in collaboration with our lab, tested the effects of AM3506 in a mouse model of fear extinction. Systemic or intra-amygdala administration of AM3506 facilitated fear extinction, and this effect was reversed by CB1 antagonist treatment. AM3506 treatment increased anandamide levels in the basolateral amygdala, and modified the expression of extinction-related kinases and phosphatases. In human subjects, individuals carrying a low-expressing FAAH variant showed quicker habituation in a fear-related fMRI task as well as lower stress reactivity in a personality test. These results raise the possible therapeutic use of AM3506 in PTSD. These findings have been submitted for publication with Dr. Holmes as corresponding author. Endocannabinoids and CB1 receptors have also been implicated in the control of pain responses as analgesic mediators. In collaboration with Dr. Yun Guan (Johns Hopkins Univ) we examined the analgesic properties of AM3506 in a rat model of neuropathic pain. Preliminary findings indicate that AM3506 treatment causes significant, CB1 receptor-mediated reduction in mechanical allodynia, but does not affect thermal hypersensitivity. These findings highlight the selectivity of anandamide action on different modalities of neuropathic pain.
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