Doc Bushwell's Chimpanzee Refuge

Sunday, January 29, 2006

CB-1 antagonists: wacky tobaccy's pharmacological legacy

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 Fen-phen was the most notorious, and was withdrawn from the market when the drug combo was linked to potentially fatal heart valve abnormalities.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."

A cartoon of CB-1 receptor is illustrated here.

Figure from D.L. Lewis, Medical College of Georgia. Prof. Lewis' site has a succinct description of the biochemistry and signaling of CB-1.

This figure below (from Dr. K. Chapman, Univ. of N. Texas) illustrates the action of endocannabinoids in pre- and postsynaptic signaling. Synapses are the junctions between nerve cells, and 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. The latter and the more abundant 2-AG are bioactive fatty acid amides derived from the fatty acid biosynthetic pathway. A spleefy cannabinoid from marijuana, 9delta-tetrahydrocannabinol (THC) is shown below the ananamide structure. 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.

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 CB1 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, ricombinant 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 infectious diseases 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.

Tuesday, January 24, 2006

The Low Channels

The cable service in my home area of central New York State has arranged the channels with what I presume are the “undesirables” clustered together at the bottom of the dial. These include CSPAN, CSPAN2 and public access. Now I might be crazy, but I truly enjoy the low channels. CSPAN seems to be a love it/hate it for most people and pretty much everybody knows what it’s about so I won’t belabor it. But then there’s public access.

Public access: The name conjures images of bad video from the polka party at the senior center or a local show concerning the intricacies of stamp collecting for those on a budget and an aversion to glue. I don’t know what the rules are for public access programming, but on our system I often see shows that were created a thousand or more miles from here. I have a funny feeling that that was not the original intent of public access. On the other hand, if the channel was limited to, say, a 100 mile radius, I’d never get to see shows like “Conservative Roundtable”. Granted, the show is a bit predictable what with the twin photo poster backdrops of a waving flag on one side matched to an in vivo embryo on the other, but where else can you watch a TV host in a cheap suit who is clearly in need of a shower and instructions on how to use a clothes iron blather on and on about the need for estate tax reform while sitting behind a desk that’s barely a step up from cardboard?

Undoubtedly the best material from the viewpoint of inadvertent humor comes from the religious shows. Two shows come to mind immediately. First there’s the lovely “House of Yahweh” which I lovingly refer to as “House of Yahoos” produced out of Texas. It’s your basic blend of end-of-times warnings and admonishments as delivered by an often smiling elderly gent who appears to have been hit over the head by a two by four a couple times too many. If he was a cartoon he’d have those little stars circling around his noggin. In light of this observation his pronouncements suddenly seem to make perfect sense. On the other end we have “Tomorrow’s World” (AKA “Dumb-morrow’s World”) out of North Carolina. The approach here is much more earnest than “House”, featuring a stern gray haired preacher who peels off quote after quote from “the good book” to support his screeds against “fornicators and homosexuals” and well, as far as I can determine, just about anyone who doesn’t agree with his narrow view of “acceptable and moral behavior”. This is end-of-times gold. He stares straight into the camera and in no uncertain terms proclaims that the end is coming, soon, and you’d better get on board if you don’t want to experience a personal global warming of a biblical magnitude. I am continually amazed at how he manages to tie in so many of society’s ills to a lack of adherence to his particular religious scheme.

These shows, as bizarre as the content can sometimes be, at the very least have semi-professional production standards even though they are boring at best. Hey, I don’t expect great cinematography with my free inadvertent humor. Every now and then though, a real jewel pops up. No, I’m not talking about the local evangelical services that they broadcast, although I must admit that watching a bunch of pudgy, middle class clones sway back and forth to an insipid musical accompaniment makes me giggle (gotta keep it simple so the nice white folks can follow the beat).

The other day I saw something that made me do a double take. I think it was a local broadcast but I’m not sure. Whatever it was, they had decided to use an extreme amount of video compression while filming the minister giving his talk. The end result was that whenever the minister moved, he was surrounded by huge pixilated chunks of his body and the background. I can only imagine that the effect would be quite impressive following the ingestion of hallucinogenic aids (not that I recommend that sort of thing). But that wasn’t the craziest thing. The truly wacky part was the subject and detail of his talk. Unfortunately, I had missed the very beginning, but the minister was apparently referring to the relatively recent announcement of “Mitochondrial Eve” to prove a literal interpretation of Genesis. I don’t know if this guy’s an end-of-times pusher like our other TV friends, but if he is, he’s certain that the ride ain’t gonna last more than 6500 years. As anyone who is familiar with Mitochondrial Eve will have figured out by now, this fellow completely misunderstood and misapplied the results. He went to great pains, though, to explain how these scientists had, with the use of modern biology, chemistry, and so forth, essentially proved that the Biblical Eve had existed. I’m sure his audience was duly impressed. The punch line came when he said that the researchers calculated that Eve walked the Earth 200,000 years ago. In a quick and dismissive tone he said (paraphrasing) “Of course, you can’t trust these scientists with this date. We know that it is way off. We know that the real date is 6500 years ago.” It was just so matter-of-fact that I nearly fell off the couch. I wonder how many of his so-called “flock” understood that he was denigrating the parts of science that didn’t fit his world view, misinterpreting the parts that could be bent to conform, and ultimately hijacking the credibility of science for his uses while trashing it in favor of blind faith at the same time? The hypocrisy was monumental.

As the comedian said, “You can’t write this stuff it’s so good.”

Sunday, January 22, 2006

A Darwinian fundamentalist

This short n' sweet interview with Daniel Dennett (italics - D. Solomon, bold text - Dennett) appeared in this morning's NYT's Sunday magazine. His comment on the strong human tendency to ascribe "agency in things that are not agents" is noteworthy. Faith and religion may be byproducts of humans' ability to recognize others-than-the-self, and to conceive of another's existence when the other is out of sight. Dennett's comment on death, and the inability to "turn off" the deceased's existence speaks to this. Further, this recognition of others, even when not present, can be transposed to objects without sentience, like thunder and lightning or a rock. Although the latter extrapolations have no adaptive benefit, the conception of other-than-self undoubtedly does to cerebrally complex and highly social humans. Thus, it is a strong trait, that "hair-trigger tendency of which Dennett speaks. There was a good article about this in the December 2005 issue of the Atlantic Monthly: Is God an Accident?" I read this in its entirety last November while visiting my mother, an Atlantic Monthly subscriber ( and a good moderate Methodist who does not fear new ideas). I have yet to spring for the online article for my records.

Also a worthwhile read in today's NYT magazine: The Animal Self by Charles Siebert. It's a good read on the field of animal personality.

There are some underlying themes in both articles. Among them is this: never underestimate the power of neurotransmitters, synaptic networks and all their interactions with experience and environment.

January 22, 2006
Questions for Daniel C. Dennett
The Nonbeliever. Interview by DEBORAH SOLOMON, New York Times Magazine

Q: How could you, as a longtime professor of philosophy at Tufts University, write a book that promotes the idea that religious devotion is a function of biology? Why would you hold a scientist's microscope to something as intangible as belief?

I don't know about you, but I find St. Paul's and St. Peter's pretty physical.

But your new book, "Breaking the Spell: Religion as a Natural Phenomenon," is not about cathedrals. It's about religious belief, which cannot be dissected in a lab as if it were a disease.

That itself is a scientific claim, and I think it is false. Belief can be explained in much the way that cancer can. I think the time has come to shed our taboo that says, "Oh, let's just tiptoe by this, we don't have to study this." People think they know a lot about religion. But they don't know.

So what can you tell us about God?

Certainly the idea of a God that can answer prayers and whom you can talk to, and who intervenes in the world - that's a hopeless idea. There is no such thing.

Yet faith, by definition, means believing in something whose existence cannot be proved scientifically. If we knew for sure that God existed, it would not require a leap of faith to believe in him.

Isn't it interesting that you want to take that leap? Why do you want to take that leap? Why does our craving for God persist? It may be that we need it for something. It may be that we don't need it, and it is left over from something that we used to be. There are lots of biological possibilities.

Didn't religion spring up in its earliest forms in connection with the weather, the desire to make sense of rain and lightning?

We have a built-in, very potent hair-trigger tendency to find agency in things that are not agents, like snow falling off the roof.

There was so much infant mortality in the past, which must have played a large role in encouraging people to believe in an afterlife.

When a person dies, we can't just turn that off. We go on thinking about that person as if that person were still alive. Our inability to turn off our people-seer and our people-hearer naturally turns into our hallucinations of ghosts, our sense that they are still with us.

But they are still with us, through the process of memory.

These aren't just memories.

I take it you do not subscribe to the idea of an everlasting soul, which is part of almost every religion.

Ugh. I certainly don't believe in the soul as an enduring entity. Our brains are made of neurons, and nothing else. Nerve cells are very complicated mechanical systems. You take enough of those, and you put them together, and you get a soul.

That strikes me as a very reductive and uninteresting approach to religious feeling.

Love can be studied scientifically, too.

But what's the point of that? Wouldn't it be more worthwhile to spend your time and research money looking for a cure for AIDS?

How about if we study hatred and fear? Don't you think that would be worthwhile?

Traditionally, evolutionary biologists like Stephen Jay Gould insisted on keeping a separation between hard science and less knowable realms like religion.

He was the evolutionist laureate of the U.S., and everybody got their Darwin from Steve. The trouble was he gave a rather biased view of evolution. He called me a Darwinian fundamentalist.

Which I imagine was his idea of a put-down, since he thought evolutionists should not apply their theories to religion.

Churches make a great show about the creed, but they don't really care. A lot of the evangelicals don't really care what you believe as long as you say the right thing and do the right thing and put a lot of money in the collection box.

I take it you are not a churchgoer.

No, not really. Sometimes I go to church for the music.

Yes, the church gave us Bach, in addition to some fairly spectacular architecture and painting.

Churches have given us great treasures. Whether that pays for the harm they have done is another matter.

Saturday, January 21, 2006

Yessir, that's my baby!

The quandry: should I wait a little while before I roll over my old 401k (all company stock) to my current one or gamble and let it go for the end of Phase II?

From the Biopeer blog. There are a number of other press releases on VX-950, and no, it is not some third generation nerve gas. Just Google it.

January 10, 2006

Vertex’s VX-950 drug leads to cure for Hepatitis C

The experimental pill VX-950 launched by Vertex Pharmaceuticals has proved effective in the treatment of Hepatitis C, a liver disease that leads to liver decline, cancer and death. The results have revived hopes in the company’s claims that the pill would be helpful in reducing the treatment time of Hepatitis C to three months from the current timeframe of about a year. Moreover, VX-950, a protease inhibitor that blocks enzyme in liver cells linked to virus reproduction has been given a fast-track designation by the FDA.

According to the 14-day trial study conducted on eight patients by administering a combination treatment consisting of Vertex’s VX-950 and pegylated interferon, virus presence in patients reduced significantly by 300,000-times in a stipulated period of over two weeks. Additionally, it was also revealed that the medication was well tolerated by the patients with no reports of any kind of serious adverse effects. Typical interferon-related side effects, of mild to moderate severity, were registered in the patients that were administered with peg- IFN along with VX-950.

Meanwhile, Prudential Equity Group raised the price target on Vertex Pharmaceuticals from USD 28 to USD 37 with the announcement that positive clinical results of its experimental Hepatitis C treatment. Further the studies have also helped in soaring the market share prices of Vertex by 78 cents, which is an increase of 2.5 per cent on Nasdaq.

Doc Bushwell's safe harbor statement: the word "cure" in the title is forward-looking since data on rebound viral replication have not been reported by Vertex. Still, it's an extraordinary drop in viral load. Let's just say I'm a proud mama but I, along with VX-950's other parents, will not be making arrangements for the graduation party just yet. But we're hopeful that "our baby" will pass all its classes in Phase II and Phase III, then graduate summa cum laude to the benefit of many HCV+ patients.

Friday, January 20, 2006

On flinging bonobo scat here or in my new Funhouse

Kilgore has kindly provided me with my own sub-forum, Doc Bushwell's Funhouse o' Science on The Endorphin Cult (EC). Although bonobo scat may be tossed about freely here in the form of comments (registration not required), the Funhouse (also linked to the right) allows for more discourse. Again, you may post anonymously on the Funhouse or the EC.

Be forewarned that some of the EC content can be described at best as R-rated, and at worse, NC-17. Kilgore, the orthodox libertarian moderator, maintains an extremely light, even non-existent. hand with content, other than formatting interventions. I really like his approach since it allows for free-wheeling dialogue, as well as clever permuations of profanities, but those who are accustomed to the niceties of polite society should be aware that the EC is no tea party.

Science Blogs: a sexy Madison Avenue kind of vibe

Found in the Business section of this morning's New York Times:

Science Blogs as a Vehicle for Upscale Ads

The summary from 30,000 feet is this: advertisers are looking toward the new media of blogdom as a vehicle for hawking their wares. Seed Magazine, which focuses on the Venn diagramatic intersection of science and culture, is launching a network of science oriented blogs and plans to sell ad space to some hefty corportations. Seed Media is engaged in a marketing research study aimed at examining the relationship beween consumers and science in collaboration with JWT New York. Here's snippet of the results, excerpted from the NYT article:

The research has identified about 20 million Americans, 7 percent of the population, who are labeled in the study as "Leonardos," named after da Vinci for their avid, Renaissance-style interest in science as well as subjects like art and politics.

Leonardos are mostly male, in their 30's and middle to upper class, said Eliza Esquivel, a planner at JWT New York who is working with Ms. Cortizo on the study.

The Chimp Refuge may never qualify as a lofty enough addition to Seed's select group. After all, our contributions are a bit scurrilous, and my menopausally diffuse brain causes me to veer from the scientific realm now and then. But lofty or not, I am proud to claim a couple of articulate and rakish Leonardos for my blog team.

The links to Seed Magazine and ScienceBlogs are now on the Refuge. Note that a couple of familiar faces, Pharyngula and Gene Expression, are now hosted on ScienceBlogs. Please update your links to these fine blogs. Now I will anxiously await the colorful Viagra, Propecia and Nexium ads contaminating the purity of the overwhelmingly academic offerings on ScienceBlogs. Welcome to my world, baby!

Coming to the Refuge soon: cannabinoid receptors and botanical pornography!