The results of a Phase II clinical trial with BAY-387271 are awaited with great excitement. Also highlighted during the conference were various derivatives of cannabidiol. Particularly interesting in this regard was the compound -7-hydroxy-4#- dimethylheptyl-cannabidiol a hydroxylated, dimethylheptylated cannabidiol, structurally related to HU-210. Like D9 -THC, 7-OH-DMH-CBD is a potent inhibitor of electrically evoked contractions in the mouse vas differens. However, 7-OH-DMH-CBD does not significantly bind to either CB1 or CB2 receptors and its inhibitory effects on muscle contractility are not blocked by CB1 or CB2 receptor antagonists, suggesting that the compound may target an as-yet-uncharacterized cannabinoid-like receptor. This hypothesis is reinforced by pharmacological experiments, which suggest that 7-OH-DMH-CBD displays anti-inflammatory and intestinal-relaxing properties, but does not exert overt psychoactive effects in mice. However, the nature of this hypothetical receptor and its relationship to other cannabinoid-like sites in the vasculature and in the brain hippocampus remains to be determined.Another way to reduce central side effects is to target peripheral CB2 receptors, which are expressed in the brain only during inflammatory states and even then are limited to microglia. Selective CB2 receptor agonists include the compounds AM1241 and HU-308 . Compounds of this type offer a great deal of promise in the treatment of pain and inflammation. Studies conducted on multiple animal models of pain have shown that the CB2-selective agonist AM1241 has robust analgesic effects and is very potent in neuropathic pain models.
These effects are maintained in CB1-deficient,weed growing accessories but not in CB2-deficient mice.Cannabinoid analogs are currently in development or being tested by Astra, Bayer, Endo, GSK, GW Pharmaceuticals, Indevus, Kadmus Pharmaceuticals, MAKScientific, and Pharmos. Some of the obvious issues in drug development are efficacy, side effects, and regulatory scheduling. With regard to efficacy, the primary clinical targets are pain, stroke, nausea, appetite, and cough. Potential side effects in addition to the well-known central psychotropic actions include cardiovascular and immune perturbations, as well as fertility problems. Finally, a major question from the perspective of drug industry is one of regulatory scheduling: that is, whether any drug acting either directly or indirectly through the endocannabinoid system will be subject to the restrictive scheduling of D9 -THC, or whether scheduling will be determined by side effects, as is the case with most drugs.A large number of pharmaceutical companies have started active CB1 antagonist programs, mostly as a result of the clinical success of SR141716A , the first CB1 antagonist to be developed. This molecule has successfully completed Phase III studies and is anticipated to become available within a year for the treatment of obesity and tobacco addiction. Rimonabant is an inverse CB1 agonist with a Ki of 11 nM at the CB1 receptors and 1640 nM at CB2. Additional agents currently in development include SLV-326 and LY320135 . However, all of these compounds are inverse agonists. A series of neutral antagonists has been generated, but remains not as well characterized in the literature. Examples of this class are the compounds O-2654 and AM5171 . As noted above, therapeutic areas for cannabinoid antagonists include obesity, drug addiction and perhaps CNS disorders.
The mechanism by which cannabinoid antagonists exert their anti-obesity effects is still not fully understood. Data on rimonabant presented at the workshop identified two possibilities. First, there is a loss of appetite.Mutant mice that are deficient in CB1 receptors eat less than wild-type controls. Second, there is an increase in metabolic rate and a loss of fat mass. These effects may be linked, on the one hand, to the ability of rimonabant to affect corticotropin-releasing hormone , as suggested by the fact that CB1 receptors colocalize with CRH receptors in the hypothalamus. This may be significant for explaining the drug’s effects on appetite drive, as it is known that CRH is anorexigenic. On the other hand, mice that lack CB1 receptors display a hyperactivity of the hypothalamicpituitary-adrenal axis, with increases in both ACTH and corticosterone. This phenotype may be important in regard to overall metabolic rate. Another possible mediator of the long-lasting effect on body weight reduction unrelated to altered food intake is the adipocyte, because CB1 receptor activation causes lipogenesis, which is blocked by rimonabant.CB1 cannabinoid receptors are present on the cell surface of neurons within the brain reward circuitry. Furthermore, endocannabinoids may be released from dopamine neurons in the ventral tegmental area , and from medium spiny neurons in the nucleus accumbens of the brain reward circuit. Additionally, endocannabinoids and D9 -THC activate CB1 receptors and by doing so regulate reward strength and drug craving. Though we do not know how this occurs, it is likely that these mechanisms extend to all drugs of abuse, because collectively these drugs show the propensity to increase VTA dopamine neuron activity, which might be coupled to augmented endocannabinoid production from the dopamine neurons themselves. Finally, cannabinoid receptor antagonists block the effects of endocannabinoids in these reward circuits. Preclinical work shows that priming injections of cannabinoid agonists reinstate heroin-seeking behavior after a prolonged period of abstinence in rats trained to self-administer heroin.
Additionally, rimonabant significantly attenuates cannabinoid-induced reinstatement of heroinseeking behavior. All these findings clearly support the hypothesis of a functional interaction between opioid and cannabinoid systems in the neurobiological mechanisms of relapse and might suggest a potential clinical use of cannabinoid antagonists for preventing relapse to heroin abuse. It has also been shown that cannabinoid antagonists can prevent drug reinstatement with cocaine, alcohol, and nicotine. Thus, it seems that the future of cannabinoid antagonists in substance abuse treatment is particularly promising, especially in the clinical setting, where poly drug abuse is exceedingly more common than isolated single-drug abuse.The available data suggest that CB1 antagonism produces relatively mild side effects in people. Yet several potential risks were discussed and three in particular received a great deal of attention. First, the possibility of neuropsychiatric sequelae, such as anhedonia and anxiety: preclinical studies have consistently shown such effects in animals, though they have not yet been observed in the clinic. Second, pain and hyperalgesia, because of the pervasive role played by the endocannabinoid system in the control of pain processing. Last, hypertension, as indicated by the contribution of the endocannabinoids to blood pressure regulation and the pressor effects of rimonabant in animal models of hypertension.The endocannabinoid signaling system differs from classical neurotransmitter systems, picking up where classical neurotransmitters leave off. That is, the activation of receptors initiates a series of chemical events that leads to the release of endocannabinoids from the postsynaptic spine e the final step of which is the enzymatic production and subsequent release of anandamide and/or 2-AG. Once released, the endocannabinoids are then directed to the presynaptic cell and the CB1 receptor responds by inhibiting further release of that cell’s neurotransmitters. The termination of this cascade is accomplished via a transporter that internalizes the endocannabinoids,cannabis drying rack ideas after which intracellular enzymes such as fatty-acid amide hydrolase break them down. There is a general consensus that endocannabinoids are transported into cells via a facilitated diffusion mechanism. This process may differ both kinetically and pharmacologically from cell to cell. In brain neurons, endocannabinoid transport is blocked by certain agents, which include the compounds AM404, OMDM-8 and AM1172 . However, the pharmacological properties of these drugs in vivo are only partially understood. Once inside cells, endocannabinoids are hydrolyzed by three principal enzyme systems.
FAAH is a key enzyme of anandamide deactivation in the brain. Potent and selective FAAH inhibitors have been developed and shown to exert profound antianxiety and antihypertensive effects in animals. The latter effects were discussed at length at the workshop, highlighting the important role of anandamide in two important examples of vascular allostasis e shock and hypertension. In addition to FAAH, another amide hydrolase has been recently characterized, which may participate in the degradation of anandamide and other fatty-acid ethanolamides such as oleoylethanolamine . This amidase prefers acid pH values and has a different tissue distribution than FAAH, being notably high in lung, spleen and inflammatory cells. Inhibitors of this enzyme are being developed. Finally, 2-AG is hydrolyzed by an enzymatic system separate from FAAH, which probably involvesa monoacylglycerol lipase recently cloned from the rat brain. Inhibitors of this enzyme are currently under development.What are the therapeutic advantages and drawbacks of using a direct agonist vs. an indirect agonist? Several parallels can be drawn to the well-known SSRIs , which have shown such powerful and useful therapeutic applications in effecting indirect agonism of the serotonergic system. Indeed, there is ample evidence that pharmacological profiles for the indirectly-acting agonists can generally be attributed to enhanced selectivity based on more localized action. A prime reason for favoring the indirect agonism approach is the possibility of obtaining new drugs devoid of the psychoactive effects and perceived abuse potential of directly acting CB1 agonists. If we accept the postulate of on-demand modulation of endocannabinoid signaling as contributing to some disease states, we are likely to witness the development of more specific medications acting indirectly such as inhibitors of cannabinoid uptake or breakdown.An avenue through which endocannabinoid-like fatty-acid ethanolamides have been shown to accomplish their effects is through binding to intracellular receptors like the ligand-activated transcription factor peroxisome proliferators-activate receptor-a . OEA exerts profound satiety-inducing, weight-reducing and anti-inflammatory effects in rodents, which are absent in mice deficient in PPAR-a and are closely mimicked by synthetic PPAR-a agonists. Furthermore, OEA was found to bind to and activate PPAR-a with high affinity in vitro. These findings suggest that OEA is an endogenous PPAR-a agonist involved in the regulation of energy balance. An analogous role has been recently suggested for palmitoylethanolamide, the antinflammatory properties of which have been known for decades and are now been exploited in veterinary medicine.North America comprises the world’s largest drug market and evidences the highest drug related mortality rate in the world , 2011. Within the United States the problem of prescription drug misuse and opioid misuse in particular, has reached epidemic proportions. Pain relievers were the most commonly misused drug in the psychotherapeutics category from 2002 to 2011 , 2012 and from 2004 to 2011, the number of medical emergencies involving opioids increased by 183% . Abuse of prescription drugs is a significant public health problem, associated with high costs both to the health care system and to the individuals who use them. From an economic perspective, it is estimated that opioid misusers’ medical care costs are eight times greater than those of non-misusers . Mortality due to prescription drug use is a significant cause of death in the United States, accounting for 36% of all poisoning deaths in 2007, a number that tripled from 1999 to 2007 . It is estimated that 0.04% of individuals receiving a prescription opioid have a fatal overdose, with the odds of mortality higher among those receiving an opioid for pain . Identifying patients who misuse these substances is often difficult, since clinicians must disentangle legitimate pain management needs from possible abuse. When opioid abuse or dependence develops, patients’ medical treatment is complicated by tolerance, withdrawal, or potential overdose. Little is known about factors that may place individuals at risk for the development of prescription drug use disorders. As a recent editorial indicates, these individuals may differ significantly from those who are typically studied in substance use disorder research; specifically, many at risk for opioid use disorders may not have a history of illicit drug use prior to developing a problem with opioids . Since the rates of prescribing opioids, state by state, are linked to mortality due to overdose, it is clear that a prescription of an opioid places individuals at risk for eventual misuse . Researchers have attempted to identify factors that may predict later drug abuse and dependence. Earlier age of non-medical use of prescription drugs, earlier initiation of alcohol use, family history of alcoholism, and poly drug abuse predicted greater risk for developing prescription drug abuse or dependence . Previous research has found that there are particular demographic variables that place individuals at higher risk for the development of a diagnosis of opioid abuse and dependence. Specifically, individuals who are younger and male were more likely to develop abuse and dependence.