Natural analgesic products

Look SA, Fenical W, Jacobs RS, Clardy J (1986) The pseudopterosins anti-inflammatory and analgesic natural products from the sea whip Pseudopterogorgia elisabethae. Proc Natl Acad Sci USA 83 6238-6240... 

A recent example demonstrates that corals rely on induced biosynthesis of terpenes as a dynamic defense strategy as well. The induction of terpenoid secondary metabolites was observed in the sea whip Pseudopterogorgia elisabethae [162]. Levels of pseudopterosins 89-92, a group of diterpene glycosides with anti-inflammatory and analgesic properties (Scheme 23) [163-165], are increased in response predation by the mollusk Cyphoma gibbosum. First bioassays indicate that these natural products are involved in the chemical defense. 

One of these natural products, epibatidine (1) was isolated from the skin of the Ecuadorian frog, Epipedobates tricolor, by Daly and coworkers in 1992 and found to have powerful analgesic activity and high binding affinity to nicotinic acetylcholine receptors (uAChRs). This is reminiscent of a classical apphcation of nicotine (2), being stractmally related to 1 [3]. 

Morphine is a complex natural product with potent analgesic properties... 

During the nineteenth century, chemists had a good deal of success in isolating and purifying natural products from plant sources. Morphine was isolated as a pure compound from crude opium in 1804. Quinine was isolated from the bark of the cinchona tree in 1820 and was initially employed as a fever reducer. However, its effectiveness against malaria was soon discovered and it found an alternative highly important medical use. Sodium salicylate was isolated from the bark of the willow tree in 1821 and was also shown to have analgesic, antipyretic, and antiinflammatory properties. It took an additional 76 years, until 1897, to synthesize the acetyl derivative, acetylsalicyclic acid, commonly known as aspirin. 

McCurdy CR, Scully SS, Analgesic substances derived from natural products (natureceuticals). Life Sci 78 476—484, 2005. 

Marine natural products are also on trial as CNS aids (SNX-111, a peptide from mollusks, which is a nonaddictive analgesic agent 100-1,000 fold more potent than morphine, now in clinical phase III) and against pathogenic fimgi (15G256y, a macrolide from filamentous fimgi). 

Historically, plant-based natural products have been a source of useful drugs. The analgesic opiates come from the poppy plant. Digitalis for congestive heart failure was first isolated from the foxglove plant. Various antibiotics (penicillin) and anticancer agents (taxol) are derived from natural product sources. There are numerous other examples. 

Nature has been a potential source of therapeutic agents for thousands of years. An impressive number of modem dmgs have been derived from natural sources. Over the last century, a number of top selling dmgs have been developed from natural products. Anticancer dmg vincristine from Vinca rosea, narcotic analgesic morphine from Papaver somniferum, antimalarial dmg artemisinin from Artemisia annua, anticancer dmg Taxol from Taxus brevifolia and antibiotic peniciUins from Penicillium ssp. are just a few examples. 

The narcotic analgesics are also called the opioids because they are related structurally to the natural products of the opium poppy. The medicial properties of opium have been known for thousands of years. It has been used by shamans and medicine men and women for pain, sleep, coughing, and diarrhea. The key chemical compound among the 20 or so isolated from the resin of the... 

The natural product epibatidine was the starting point for worldwide activities towards the discovery of nicotinic analgesics. Besides its unusual antinociceptive potency (review Bai et al., 1997) its exceptional structure combines a scarce chloropyridine moiety with a 7-aza-norbornane (7-azabicyclo[2.2.1]heptane) bicycle which has never before been found in a natural product before. In 1994 the absolute configuration of natural (+)-epibatidine was determined to be IR RAS (Fletcher et al., 1994). Initial patents on epibatidine and close structural analogs were filed by the U.S. Department of Health (Daly et al., 1993, 1995). 

Epibatidine was shown to be a very potent and selective agonistic ligand of nicotinic acetylcholine receptors. This natural product is effective in various animal models of pain through a pronounced nAChR agonistic mechanism (Ki <100 pm) which is accompanied by severe and nACh-related side-effects (Corey et al. 1993 Rupniak et al., 1994 Boyce et al., 2000). A clear differentiation between antinociceptive activity in animal models of pain and toxic side-effects cannot be determined. Nevertheless there is some activity directed towards the development of epibatidine as an analgesic (Bai et al., 1997). 

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