Dr. Joan Bushwell's Chimpanzee Refuge

Today, the FDA’s Endocrinologic and Metabologic Advisory Committee reviews rimonabant, the cannabinoid receptor antagonist developed by Sanofi-Aventis, for recommendations, or lack thereof, as an anti-obesity medication. Rimonabant was approved in Europe for limited cohorts of obese patients, but rejected as an anti-smoking medication. Approval for marketing rimonabant in the US is pending next month, and the advisory committee’s assessment will weigh heavily on this decision.

There are other ‘bants in the pharma pipeline so it should be interesting to see how today’s decision plays out. A major concern is the increased incidence of psychiatric effects, e.g., from the NJ Star Ledger, 06/12/2007, FDA links obesity drug to suicides: Sanofi-Aventis studies reveal psychiatric events.

As we await the FDA’s decision, our adipocytes aquiver with anticipation, please allow me to distract you from that box of Hostess Twinkies and the nearby six pack of Bud with my scintillating historical bloggery on cannabinoid receptors, accompanied by my usual gentle measured opinion on obesity drugs.

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Jan. 29, 2006

Now that we’re a month into 2006, let us put the War on Christmas 2005 behind us and move on to the War on Obesity. The “battle of the bulge” has been a catch phrase for years, yet waistlines, and hips and thighs and arms keep expanding. For the majority of the overweight, including myself, there is an effective answer: less calorie intake and more exercise. It works for me. It works for many people. It is not a facile process, and requires consistent self-discipline in a society prone to copious amounts of food and generous portions of lifestyle conveniences, or lifestyle stressors, which discourage activity. The medical community has firmly stated in any number of venues that obesity is a significant public health problem. The pharma industry jumped on the obesity bandwagon some years ago with mixed results. Amphetamines with all their concomitant adverse side effects were a staple in the weight loss pharmacopoeia for years, but fell from favor as newer, relatively safer antiobesity drugs arrived on the scene. Serotonin reuptake inhibitors (similar to Prozac and its relatives) were the antiobesity flavor of the month. Fen-phen was the most notorious, and was withdrawn from the market when the drug combo was linked to potentially fatal heart valve abnormalities. Meridia, also a serotonin reuptake inhibitor, remains on the market, but with a plethora of precautions. Meridia differs from the recalled Fen-phen in that the drug’s actions tend to localize in the brain’s appetitie control center, thus bypassing the heart, whereas fenfluramine caused a systemic boost in serotonin levels, thus raising the potential for heart valve damage.

Among the more recent pharmaceutical offerings are two which are coming to the FDA for reviews as reported via Reuters on Yahoo, Drug firms eye fat profits from new obesity pills, and this undoubtedly expired NYT article, 2 Approaches to the Nation’s Obesity Epidemic Coming Up for Review. The mechanisms of action of these drugs are distinct from fen-phen and Meridia.

Low dose Xenical will be submitted for approval for OTC sale. Long term studies indicate that it is a relatively benign drug in terms of adverse side effects. Because it blocks fat absorption, a side effect with great potential for embarrassment is loose stools due to the unabsorbed fat. As the earlier soft focus TV ads noted, the patient taking Xenical must do his or her part. Xenical, in addition to reduction of calorie absorption through its fat-blocking action, acts as adjunct behavior modification. If someone taking Xenical overindulges in large portions of fatty food, there will be diarrheal hell to pay. Hence, the patient is motivated to stick to a moderate diet.

Among potential anti-obesity medications moving through clinical trials is Accomplia, the other drug up for review before the FDA. Ten years ago, scientists at Sanofi, a large French pharmaceutical company, discovered the first selective antagonist (blocks or inhibits biological action) of the cannabinoid-1 (CB-1) receptor. Accomplia is the culmination of Sanofi-Aventis’ R&D, and represents a new approach to weight loss.

CB-1 and its close relative, CB-2, are members of the broader G-protein coupled receptor (GPCR) family. These receptors have characteristic 7 member transmembrane domains which span the membrane from the outer part of the cell to the inner (intracellular) region. CB-1 and CB-2 were discovered in 1988 and 1993, respectively, through research of marijuana’s active components, the cannabinoids. More research revealed the cognate endogenous ligands of the CBs in the brain: anandamide and 2-arachidonylglycerol (2-AG). These chemicals are more generally called “endocannabinoids.”

This figure below from Dr. Kent Chapman’s website illustrates the action of endocannabinoids in pre- and postsynaptic signaling. [Note added in proof: Kent Chapman is the director of the Center for Plant Lipid Research; his summary of the neuroactive properties of N-acylethanolamines is excellent.]

Synapses, the junctions between nerve cells, have directionality, hence, the “pre-” and “post-” terminology. Anandamide acts through “retrograde signaling.” Typically, water soluble neurotransmitters, glutamate for example, are released from the presynaptic neuron, flow across the junction, and bind to receptors on the postsynaptic neuron, and depending on the neurotransmitter:receptor pairing, can elicit an excitatory or inhibitory response in the postsynaptic neuron. The endocannabinoids work “backwards.” Influx of calcium ions into a postsynaptic neuron upregulates biosynthesis and release of endocannabinoids. These bind to CB-1 receptors clustered on the presynaptic neuron. Through signaling, the CB-1 receptor inhibits ion influx into the presynaptic cell and blocks release of neurotransmitters to the postsynaptic neuron. This can cause a postsynaptic neuron to “fire” or receive an excitatory stimulus since it is no longer receiving an inhibitory signal from the presynaptic neuron. In the absence of the endocannabinoid retrograde signaling, the postsynaptic neuron would be “damped down.” This a less than adequate explanation of a complex phenomenon. A proper treatment would extend beyond the scope of the Chimp Refuge, but there’s a great illustration of endocannabinoid mediated retrograde signaling in “The Brain’s Own Marijuana” in the December 2004 issue of Scientific American.

Now let’s take a look at the chemical structures of the various players in the endocannabinoid system. Below is an illustration of an endocannabinoid, ananamide (long alkyl chain with 4 unsaturated C-C bonds). The latter and the more abundant 2-AG are bioactive fatty acid amides derived from the fatty acid biosynthetic pathway. The tricyclic structure hovering around 2-AG like the scent of patchouli is a spleefy cannabinoid from marijuana, 9delta-tetrahydrocannabinol (THC). Note that these molecules share an n-pentyl “tail”, i.e., a 5 carbon alkyl chain which you can see at the lower right part of each molecule. This chain appears to be required for biological effects since if it is removed from either ananamide or THC, the molecule loses its biological effect. Ananamide and THC act as agonists and enhance the CB receptors’ functions.

CB-1 is widely distributed in the central nervous system and is the among the most abundant GPCRs in the brain. In addition to the familiar (well, to at least a handful of Chimp Refuge readers, I expect) psychotropic effects, mediates pain and appetite. The agonist effects of “medical marijuana’s” cannabinoids are well known, e.g., treatment of glaucoma, debilitating pain associated with cancer, chemotherapy-induced nausea and cachexia resulting from AIDS and cancer.

CB-1 has been the focus of intense scrutiny, but CB-2 which is located in the periphery, and predominantly in the immune system, is also shining in the spotlight because of its role in inflammation. CB-2 also appears to mediate few, if any behaviors, but appears to be associated with peripheral pain like that derived from inflammation. CB-2 and its endocannabinoid ligands are thought to be a part of a neuroimmune axis. A hot off the presses publication in the Jan. 09 issue of the Proceedings of the National Academy of Sciences USA implicates CB-2 as a regulator of bone mass.

The cannabinoid receptors thus represent a rich source of therapeutic targets. There is evidence for cannabinoid receptors distinct from CB-1 and CB-2. Not surprisingly, pharmaceutical companies and biotechs have submitted a plethora of patents and patent applications surrounding chemicals that block (antagonists) or enhance (agonist) CB-1 and CB-2 activity. Accomplia (generic name:rimonabant) is being submitted for weight loss, but the multivariate role of CB-1 suggests that targeting the receptor may be useful for other indications such as smoking cessation and psychiatric disorders, i.e., as potential antidepressants and antianxiolytics.

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Rimonabant’s structure is distinct from that of the endocannabinoids and cannabinoids. Rimonabant does not have the n-pentyl chain like THC or ananamide. The exact binding interactions of rimonabant with CB-1 have not been observed directly through X-ray diffracion. Bovine rhodopsin, a protein in the retina, is the only GPCR whose structure has been determined by this method. This serves as a model for other GPCRs, including CB-1 and CB-2. Rimonabant’s interaction with CB-1 is inferred by computer-assisted molecular modeling and mutagenesis of amino acid residues in the purported binding sites. However, even with robust mathematical modeling and in the absence of a crystal structure, sometimes it’s a best guess as to the precise nature of GPCR binding with ligands, antagonists and agonists.

Patients taking rimonabant on average lost about 10-15 pounds over the course of a year. HDL cholesterol increases in a dose dependent manner, so that’s a plus. However, significant percentages of patients dropped out of trials because of adverse side effects relative to placebo. The dark side of Accomplia is depression and anxiety. These side effects are not unanticipated. Research on the endocannabinoid system indicates that 2-AG and ananamide act to ease anxiety, and that there’s interplay between the dopaminergic system and endocannabinoids. Thus, an antagonist which blocks these actions could exacerbate anxiety and depression.

From a purely scientific standpoint, rimonabant, its clinical cousins and the CB receptors in general are way up there on the Bushwellian “Golly, ain’t it cool?” scale. The endocannabinoid signaling system is fascinating, and there are many potential targets for pharmaceutical intervention, e.g. neuropsychiatric disorders, pain and who knows…maybe osteoporosis. But I always come around to the nagging question of all the efforts and money expended to treat obesity. I admit I speak from personal bias. I have never been more than 25-30 pounds overweight, and when I make up my mind to do something about it, I lose the flab through diet and exercise. I do not know what it is like to be 100 pounds overweight. Maybe a pharmaceutical intervention would be of great benefit for the morbidly obese. For the garden variety obese patient, I’m not convinced. To harken back to my “Big Fat Golden Goose Eggs” blog entry in July 2005, the words of my colleage in medicinal chemistry still resonate: all that work to come up with a pill which will allow a 300 pound person to lose 15 pounds, and that pill had better have a squeaky clean safety profile. I’m not so sure Accomplia has that. It will be interesting to see what the FDA’s verdict is, especially since the agency is so skittish after the Vioxx debacle.

So the big fat bottom line to the pharma industry is that obesity is a large market. I know, a cheap shot. It affects me professionally because some of my group’s resources are directed toward an antiobesity target. I wrestle with the market drivers which influence discovery research since I see projects in metabolic diseases, inflammation, oncology and neurosciences which I deem more worthy of my group’s considerable talents, and yes, the impetus to realign our research efforts is often on my mind. And personally, well, if offered the choice of Accomplia or Weight Watchers, I know which one I would choose.

Comments

  1. #1 sailor
    June 14, 2007

    “Amphetamines with all their concomitant adverse side effects were a staple in the weight loss pharmacopoeia for years, but fell from favor as newer, relatively safer antiobesity drugs arrived on the scene.”

    They probably still are if done right. Take them for one week only – organize plenty of exercise, because you will have the energy and use the time of lowered appetite to change your eating habits. Coming down after the week take day in bed and make sure there is not too much food around. Consider it like a hard kick in the right direction. But don’t continue taking them or you are probably headed for both habituation and addiction.

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