Curr Drug Deliv. 2008 Oct;5(4):243-7.
Pro-drugs for indirect cannabinoids as therapeutic agents.
Ashton J.
Department of Pharmacology & Toxicology, Otago School of Medical Sciences University of Otago, PO Box 913, Dunedin 9054, New Zealand. john.ashton@stonebow.otago.ac.nz
Medicinal cannabis, cannabis extracts, and other cannabinoids are currently in use or under clinical trial investigation for the control of nausea, emesis and wasting in patients undergoing chemotherapy, the control of neuropathic pain and arthritic pain, and the control of the symptoms of multiple sclerosis. The further development of medicinal cannabinoids has been challenged with problems. These include the psychoactivity of cannabinoid CB1 receptor agonists and the lack of availability of highly selective cannabinoid receptor full agonists (for the CB1 or CB2 receptor), as well as problems of pharmacokinetics. Global activation of cannabinoid receptors is usually undesirable, and so enhancement of local endocannabinoid receptor activity with indirect cannabimimetics is an attractive strategy for therapeutic modulation of the endocannabinoid system. However, existing drugs of this type tend to be metabolized by the same enzymes as their target endocannabinoids and are not yet available in a form that is clinically useful. A potential solution to these problems may now have been suggested by the discovery that paracetamol (acetaminophen) exerts its analgesic (and probably anti-pyretic) effects by its degradation into an anandamide (an endocannabinoid) reuptake inhibitor (AM404) within the body, thus classifying it as pro-drug for an indirect cannabimimetic. Given the proven efficacy and safety of paracetamol, the challenge now is to develop related drugs, or entirely different substrates, into pro-drug indirect cannabimimetics with a similar safety profile to paracetamol but at high effective dose titrations.
(I don't buy this acetominophen bit... we'll see... but I thought that I should at least park this.)
And from the "No ****, Sherlock!" file comes this..... "suggesting that cannabinoid CB(1) receptor agonists and endocannabinoid enhancers possess antidepressant-like properties".......
Expert Opin Ther Targets. 2008 Nov;12(11):1347-66.
The cannabinoid CB1 receptor and the endocannabinoid anandamide: possible antidepressant targets.
Bambico FR, Gobbi G.
McGill University, Neurobiological Psychiatry Unit, Department of Psychiatry, Research and Training Building, 1033 Pine Avenue West, Montréal Québec, H3A 1A1, Canada.
BACKGROUND: Major depression has the highest rate of prevalence and incidence of morbidity among all mental disoders. The limited efficacies of current antidepressant treatments necessitate the development of alternative pharmacotherapies. Recent preclinical findings suggesting that cannabinoid CB(1) receptor agonists and endocannabinoid enhancers possess antidepressant-like properties, and clinical evidence that the CB(1) antagonist rimonabant increases the risk of depression and suicidality, support the notion that the endocannabinoid system represents a novel target in the treatment of mood disorders. OBJECTIVE/METHODS: To compare the mechanism of endocannabinoid enhancers and CB(1) agonists with current antidepressants and provide a rationale for a role of the endocannabinoid system in the pathology and treatment of mood disorders. RESULTS/CONCLUSION: CB(1) agonists and fatty acid amide hdyrolase (FAAH) inhibitors share mechanisms with other antidepressants: the ability to enhance central serotonergic and noradrenergic transmission and promote neurogenesis in the hippocampus. FAAH inhibitors, compared with direct CB(1) agonists, exhibit distinct pharmacological properties that quell adverse cannabinoid effects and widen the therapeutic window. Since the endocannabinoid system also plays a role in peripheral functions, side effects need to be addressed. |
