MinireviewAnalgesic substances derived from natural products (natureceuticals)
Introduction
Substances derived from natural products have been utilized since the beginning of time for various purposes including the treatment of pain. Opium, for example, has been used since the earliest records of time, some 7000 years ago. Not until the 19th century were individual components of different natural product remedies identified and purified. Today, drug discovery has become a complex field far beyond the use of only natural products. However, natural products have dominated the drug industry for many years and several marketed drugs are based on isolates from such. There has been a recent resurgence in the study of natural products, especially from the dietary supplement industry. The pharmaceutical industry has begun to revitalize programs on the screening of natural products. Academic research has continued to be a strong leader in the field of natural products, especially with respect to newly discovered chemical entities. Research in the area of pain management and drug addiction originally focused on natural products exclusively. More recently, analogs have been made from natural substances and completely synthetic compounds based on natural pharmacophores have been introduced into the market. The research and medical fields still struggle with side-effect profiles from these analgesic substances that are undesirable. Apart from rational drug design and completely novel synthetic efforts, natural products are still being investigated for novel chemical structures that may interact with known analgesic targets. In addition, orphan targets are being investigated for their potential roles in the management of pain. The pharmacology of pain has become a complex field and as more systems approaches are explored, more potential drug targets are being identified. This review will highlight some of the more recent reports of novel, naturally derived compounds that possess analgesic properties.
Section snippets
Pain mechanisms and control
Pain can be simply defined as undesirable physical or emotional experiences. Pain is the most common reason that individuals seek medical attention. It can be divided into two types, acute pain and chronic pain. Acute pain serves as a warning system to remove oneself from particular pain stimuli. Chronic pain can exist for undefined times and undefined reasons and seems to serve no clear purpose. Treatment of chronic pain is a major problem due to the use of available medications and their
Aspirin
Aspirin or acetylsalicylic acid (1, Fig. 1), derived from salicylic acid, extracted from the bark of the Willow tree (Salix alba), is one of the most widely used and available compounds for the management of mild pain. Aspirin served as the first nonsteroidal anti-inflammatory drug (NSAID) and inhibits the arachidonic acid pathway that eventually leads to the synthesis of eicosanoids, potent mediators of pain (Vane, 1971). The use of aspirin, that specifically inhibits the cyclooxygenase (COX)
Opioids
Opioid is the common name for all compounds that have the same mechanism of action as the constituents of opium. The use and abuse of opium juice from Papaver somniferum, has been know before history was recorded. All opioids interact with the endogenous opioid receptor system that presently includes four receptor subtypes (Dhawan et al., 1996) designated as mu, delta, kappa, and ORL-1 (opioid receptor like receptor). These receptors are widely distributed in the mammalian system and have been
Voltage-gated ion channels
Many natural products have been found to interact with voltage-gated ion channels. Probably the most well known ligand that blocks sodium channels is cocaine (11, Fig. 8), isolated from Erythroxylon coca (Matthews and Collins, 1983). Cocaine is mostly known and studied for its ability to block the dopamine transporter due to its ability to create a euphoric state (Kuhar et al., 1991). However, its utilization as a local anesthetic is known by its interactions through sodium channel blockage.
Acetylcholine receptors
Acetylcholine receptors are divided into two classes, the muscarinic acetylcholine receptors and the nicotinic acetylcholine receptors. These classes were identified through the utilization of the natural products, muscarine and nicotine, respectively (18 and 19, Fig. 15). There has been a well-documented role in the modulation of central nociception through these receptors however, they have not met with clinical success to date.
The muscarinic acetylcholine receptors have many known natural
Cannabinoid receptors
Another well known system involved in nociceptive processes are the cannabinoid receptors. The prototypical ligand, Δ9-tetrahydrocannabinol (21, Δ9-THC, Fig. 17), isolated from Cannabis sativa, is a non-nitrogenous lipophilic molecule that interacts with the cannabinoid G-protein coupled receptors (Gerard et al., 1990). This was most likely, the first non-nitrogenous ligand discovered that was found to interact with a GPCR. It is currently marketed in the United States for the treatment of
Vanilloid receptors
Recently vanilloid receptors (VR) have been the focus of many in the pharmaceutical and academic research groups as a potential target for new analgesics. The vanilloid receptors are ion channels and have been shown to be involved in nociceptive processes (Garcia-Martinez et al., 2002). However, their clinical potential remains to be proven. Nonetheless, several natural products have been identified as modulators of these receptors.
Capsaicin (23, Fig. 19), isolated from red hot chili peppers,
Conclusions
It is very evident that natural products have been and continue to be a valuable source of novel compounds and peptides that have the potential to serve as analgesic agents or as lead molecules for the development of such. As more research is conducted on natural products it is inevitable that more diverse compounds will be discovered and new mechanisms of action will be elucidated. With the advances made in analytical chemistry and isolation chemistry, more compounds of a purely lipid nature
Acknowledgements
The authors wish to thank Dr. Rao Rapaka from the National Institute on Drug Abuse for his constant encouragement and thoughtful insights into this review work.
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