(Press-News.org) JUPITER, FL, May 23, 2011 – Scientists from the Florida campus of The Scripps Research Institute have for the first time accomplished a laboratory synthesis of a rare natural product isolated from the bark of a plant widely employed in traditional medicine. This advance may provide the scientific foundation to develop an effective alternative to commonly prescribed narcotic pain treatments.
The study, published May 23, 2011, in an advanced online edition of the journal Nature Chemistry, defines a chemical means to access meaningful quantities of the rare natural product conolidine. Based on data from mouse models, the study also suggests that synthetic conolidine is a potent analgesic as effective as morphine in alleviating inflammatory and acute pain, with few, if any, side effects.
In recent years, there has been significant interest in developing alternatives to opiate-based pain medications such as morphine. While widely prescribed for pain, morphine has a number of adverse side effects that range from the unpleasant to the lethal, including nausea, chronic constipation, addiction, and breathing depression.
The rare natural product central to the study is derived from the bark of a widely grown tropical flowering plant Tabernaemontana divaricata (also known as crepe jasmine). Long part of traditional medicine in China, Thailand, and India, extract from the leaves has been used as an anti-inflammatory applied to wounds, while the root has been chewed to fight the pain of toothache. Other parts of the plant have been used to treat skin diseases and cancer.
Conolidine belongs to a larger class of natural products, called C5-nor stemmadenines, members of which have been described as opioid analgesics, despite a substantial discrepancy between potent in vivo analgesic properties and low affinity to opiate receptors. Conolidine is an exceptionally rare member of this family for which no therapeutically relevant properties had ever been described. Despite the potential value of conolidine and related C5-nor stemmadenines as leads for therapeutics, efficient methods to prepare these molecules were lacking.
"This was a classic problem in chemical synthesis," said Glenn Micalizio, an associate professor in the Department of Chemistry, who initiated and directed the study, "which we were able to solve effectively and efficiently¬¬—an achievement that made subsequent assessment of the potential therapeutic properties of this rare natural product possible."
Micalizio and his colleagues began working on the synthesis of the molecule after they arrived at Scripps Florida in 2008.
Testing For Potency
Once the synthesis was complete, research shifted to pharmacology for evaluation. The pharmacological assessment, performed in the laboratory of Scripps Florida Associate Professor Laura Bohn, showed that the new synthetic compound has surprisingly potent analgesic properties.
"Her pharmacological studies confirmed that while it's not an opiate, it's nearly as potent as morphine," Micalizio said.
In various models of pain, the new synthetic compound performed spectacularly, suppressing acute pain and inflammatory-derived pain, two key measures of efficacy. Not only that, but the new compound passed easily through the blood-brain barrier, and was present in the brain and blood at relatively high concentrations up to four hours after injection.
Bohn herself was surprised by the compound's potency and by the fact it so readily enters the brain.
"While the pain-relieving properties are encouraging, we are still challenged with elucidating the mechanism of action," she said. "After pursuing more than 50 probable cellular targets, we are still left without a primary mechanism."
So far, the compound has shown remarkably few, if any, side effects, but that is something of a double-edged sword.
"The lack of side effects makes it a very good candidate for development," Bohn said. "On the other hand, if there were side effects, they might provide additional clues as to how the compound works at the molecular level."
That remains a mystery. While the synthetic compound might be as effective as morphine, it doesn't act at any of the receptors associated with opiates. In fact, it misses most of the major neurotransmitter receptors completely, suggesting it may be highly tuned towards relieving pain while not producing multiple side effects. While still in the early stages of development, further characterizations of conolidine may suggest further development as a human therapeutic for the treatment of pain.
INFORMATION:
The first author of the study, "Synthesis of Conolidine, a Potent Non-Opioid Analgesic for Tonic and Persistent Pain," is Michael A. Tarselli of Scripps Research. Other authors include Kirsten M. Raehal, Alex K. Brasher, John M. Streicher, Chad Groer, and Michael D. Cameron, also of Scripps Research.
This research was made possible by Scripps Florida start-up funds, resulting from a one-time appropriation of federal economic development funds by the State of Florida, as well as support from Palm Beach County.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neuroscience, and vaccine development, as well as for its insights into autoimmune, cardiovascular, and infectious disease. Headquartered in La Jolla, California, the institute also includes a campus in Jupiter, Florida, where scientists focus on drug discovery and technology development in addition to basic biomedical science. Scripps Research currently employs about 3,000 scientists, staff, postdoctoral fellows, and graduate students on its two campuses. The institute's graduate program, which awards Ph.D. degrees in biology and chemistry, is ranked among the top ten such programs in the nation. For more information, see www.scripps.edu.
END
Lombard, IL, May 23, 2011 – Headache is a very common complaint, with over 90% of all persons experiencing a headache at some time in their lives. Headaches commonly are tension-type (TTH) or migraine. They have high socioeconomic impact and can disturb most daily activities. Treatments range from pharmacologic to behavioral interventions. In a study published online today in the Journal of Manipulative and Physiological Therapeutics, a group of Dutch researchers analyzed 119 randomized controlled clinical trials (RCTs) and determined the magnitude of placebo effect and ...
Raleigh criminal attorney Patrick Roberts at the Roberts Law Group PLLC defended a North Carolina man against the statutory rape charges.
A man who was caught engaging in sexual acts with a minor by the young woman's mother pled guilty to a misdemeanor in exchange for the dismissal of more serious statutory rape charges. The man pled guilty to contributing to the delinquency of a minor and assault on a female.
The man fell prey to a common situation in North Carolina - the alleged victim, a girl under 16 years old, lied about her age on a social networking website. ...
WINSTON-SALEM, N.C. – Monday, May 23, 2011 – New findings out of Wake Forest Baptist Medical Center reveal that a common test may be useful in predicting early death in individuals with diabetes.
The study appears in the May issue of Diabetes Care.
"People with diabetes are already at high risk of developing heart disease and experiencing an early death," said Donald W. Bowden, Ph.D., the director of the Center for Diabetes Research at Wake Forest Baptist and lead investigator. "With this study, we've discovered that we can identify a subset of individuals within ...
How well a family recovers from a natural catastrophe may be tied to the household's pre-disaster make up and socio-economic status. In a recent study, Dr. Michael Rendall of the RAND Corporation compared the number of households in New Orleans, LA that broke up following Hurricane Katrina to the national rate of household break-ups over an equivalent period. An estimated 1.3 million people fled the Gulf Coast during that emergency in 2005 – the largest urban evacuation America has ever seen. The results are published today in the Journal of Marriage and Family.
Relying ...
Jerusalem, May 23, 2011 – A little bitter with a little sweet, in the form of a nano-complex dietary supplement taken before meals, can result in a substantial reduction of fat and sugar absorption in the body, Hebrew University of Jerusalem and Harvard University researchers have found.
The researchers previously showed that naringenin, the molecule responsible for the bitter taste in grapefruits, could potentially be used in the treatment of diabetes, arteriosclerosis and hyper-metabolism.
However, the absorption of naringenin in its natural form is very low. To ...
The Wine Industry Technology Symposium (WITS), the premier event showcasing innovation and strategic use of information technology and services for the wine industry, announced headline speakers for its seventh annual conference July 12-13, 2011 at the Marriot Napa Valley.
The symposium will open with a technology showcase and hands on experiential workshops on the afternoon of Tuesday, July 12, but the main event takes place on Wednesday, July 13 with the general session and keynote speakers.
Tim Bucher's Keynote Address is titled "Technology and Innovation"
What ...
New scientific evidence challenges a popular conception that behaviours such as repetitive hand-washing, characteristic of obsessive-compulsive disorder (OCD), are carried out in response to disturbing obsessive fears.
The study, conducted at the University of Cambridge in collaboration with the University of Amsterdam, found that in the case of OCD the behaviours themselves (the compulsions) might be the precursors to the disorder, and that obsessions may simply be the brain's way of justifying these behaviours. The research provides important insight into how the ...
Johns Hopkins scientists say that a newly discovered "survival protein" protects the brain against the effects of stroke in rodent brain tissue by interfering with a particular kind of cell death that's also implicated in complications from diabetes and heart attack.
Reporting in the May 22 advance online edition of Nature Medicine, the Johns Hopkins team says it exploited the fact that when brain tissue is subjected to a stressful but not lethal insult a defense response occurs that protects cells from subsequent insult. The scientists dissected this preconditioning ...
WASHINGTON – Praying about health issues dramatically increased among American adults over the past three decades, rising 36 percent between 1999 and 2007, according to a study published by the American Psychological Association.
Researchers analyzed data from the Centers for Disease Control and Prevention's 1999, 2002 and 2007 National Health Interview Surveys for an article in the May issue of the APA journal Psychology of Religion and Spirituality. The study primarily focused on comparisons of results between the 2002 and 2007 surveys, which included, respectively, ...
A new study published in the American Journal of Transplantation reveals that HIV-infected deceased donors represent a potentially novel source of organs for HIV-infected transplant candidates that could decrease waitlist deaths and even shorten the national waitlist.
For patients with HIV, there is an increased chance of dying while awaiting transplantation, as the HIV itself causes the risk of dying on the waiting list to be higher. The option of deceased donors who were also infected with HIV could shorten this wait time. However, this is now illegal due to a 1988 ...
