Pro-Drugs for Indirect Cannabinoids as Therapeutic Agents

Abstract

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.

Peripheral antinociceptive effect of anandamide and drugs that affect the endocannabinoid system on the formalin test in normal and streptozotocin-diabetic rats

“…The antinociceptive effect of systemic treatment with AM404 has already been reported in models of acute, persistent, inflammatory (Borsani et al, 2007) and neuropathic pain induced by chronic constriction injury of sciatic nerve (La Rana et al, 2008). It has proposed advantages in relation of the use of agents that indirectly increase endocannabinoids levels as AM404 since the incidence of psychoactive effects of cannabinoids is reduced (Ashton, 2008). The antinociceptive effect of AM404 has been related to the impediment of endocannabinoid transport, responsible to reuptake AEA and 2-AG (Ashton, 2008), thus increasing endocannabinoid-mediated modulation of pain (Hillard and Campbell, 1997).…”

“…It has proposed advantages in relation of the use of agents that indirectly increase endocannabinoids levels as AM404 since the incidence of psychoactive effects of cannabinoids is reduced (Ashton, 2008). The antinociceptive effect of AM404 has been related to the impediment of endocannabinoid transport, responsible to reuptake AEA and 2-AG (Ashton, 2008), thus increasing endocannabinoid-mediated modulation of pain (Hillard and Campbell, 1997). AM404 is also able to decrease the number of Fos-positive neurons in superficial layers on dorsal root ganglia after paw formalin injection (Borsani et al, 2007), a possible signal of negative modulation of nociceptive input and consequently, a reduction of nociceptive behaviors.…”

“…ACEA is closely related to AEA (Ashton, 2008) and has presented encouraging results for treatment of seizures (Van der Stelt and Di Marzo, 2004), Alzheimer's disease (Haghani et al, 2011) and pain (Mallet et al, 2008), even when injected intraplantarlly (Potenzieri et al, 2009), due to well known neuroprotective properties of cannabinoids (Haghani et al, 2011;Van der Stelt and Di Marzo, 2004). When administered spinally, ACEA was able to selectively inhibit discharges in C and Ad fibers in a CB1 receptor dependent mechanism, without affecting proprioception (Kelly and Chapman, 2001).…”

El tratamiento del cannabis en la prensa española

“…Por otro lado, también podemos encontrar nume rosa literatura científica que demuestra el potencial terapéutico del cannabis (Abanades, Cabrero, Fiz & Farré, 2005;Ashton, 2008;Callado, 2012;Ditchfield & Thomas, 2014;Durán, Laporte & Capellà, 2004;Elphick & Egertova, 2001). En los últimos años se han incrementado considerablemente los estudios sobre las aplicaciones médicas de la marihuana, proceso que, según Ramos y Fernández (2000), está más relacio nado "con el reciente descubrimiento de la existencia de un sistema cannabinoides endógeno que con las descripciones realizadas por algunos consumidores sobre dichas propiedades curativas" (p. 20).…”

The application of drug dose equivalence in the quantitative analysis of receptor occupation and drug combinations

“…Although the exact mechanism of analgesic action of acetaminophen (paracetamol) is not fully known, an action on the central nervous system is suspected (see Ashton, 2008). When administered into either the spinal cord (intrathecal infusion) or into the brain (intracerebroventricular infusion), acetaminophen produces an antinociceptive (analgesic) effect in mice.…”