Novel analgesics

CP-55,940 (8.5) was developed during the search for novel analgesics [146]. Although it is more potent than morphine it was never approved. Nevertheless, in its tritium-labeled form it became a very important tool for research and helped in the first identification of the cannabinoid receptor. 

FAAH was originally purified and cloned from rat liver microsomes and is able to catalyse the hydrolysis of anandamide and 2-AG, in addition to other long-chain fatty acid amides [25]. Studies into the structure and role of this enzyme have generated interest in the potential therapeutic applications of FAAH inhibitors [26-28]. FAAH knock-out mouse brains contained 15-fold higher levels of anandamide than their wild-type counterparts and these animals have also been shown to be more responsive to exogenously administered anandamide [29]. These animals also showed a reduced response to painful stimuli, supporting the hypothesis that FAAH inhibition may provide novel analgesics. Levels of 2-AG were not elevated in the FAAH knock-out animals, apparently due to the existence of alternative metabolic fates for this compound [30]. 

Collin, E., Frechilla, D., Pohl, M., Bourgoin, S., Mauborgne, A., Cesselin, F. Differential effects of the novel analgesic S12813-4, on the spinal release of substance P and calcitonin gene-related peptide-like materials in the rat, Naunyn-Schmiedeberg s Arch. Pharmacol. 1994, 349, 387-393. 

Chizh, B.A., Hennies, H., Wnendt S. P2X receptors as a target for the development of novel analgesics where do we go from where we are , In 8th Mainzer Forum Medicinal Chemistry, 29 September 2000, Institute of Pharmacy, Johannes Gutenberg-Universitat, Mainz (Germany), Abstract pp. 64-66. 

Stadler M, Hellwig V, Mayer-Bartschmid, Denzer D, Wiese B, Burkhardt N (2005) Novel Analgesic Triglycerides from Cultures of Agaricus macrosporus and Other Basidiomycetes as Selective Inhibitors of Neurolysin. J Antibiot 58 775... 

DeHaven-Hudkins DL, Dolle RE. Peripherally restricted opioid agonists as novel analgesic agents. Curr Pharm Des. 2004 10 743-757. 

Animal and human clinical studies demonstrate that both endogenous and exogenous opioids can also produce opioid-mediated analgesia at sites outside the CNS. Pain associated with inflammation seems especially sensitive to these peripheral opioid actions. The identification of functional p receptors on the peripheral terminals of sensory neurons supports this hypothesis. Furthermore, activation of peripheral preceptors results in a decrease in sensory neuron activity and transmitter release. Peripheral administration of opioids, eg, into the knees of patients undergoing arthroscopic knee surgery, has shown some clinical benefit. If they can be developed, opioids selective for a peripheral site would be useful adjuncts in the treatment of inflammatory pain (see Ion Channels Novel Analgesics). Moreover, new peripherally acting dynorphins may provide a novel means to treat visceral pain. 

Carlsson K-H, Jurna I (1987) Depression by flupirtine, a novel analgesic agent, of motor and sensory responses of the nociceptive system in the rat spinal cord. Eur J Pharmacol 143 89-99... 

The side effects of a novel analgesic are of major relevance from a clinical point of view. To date most synthetic agents and variants of natural products... 

Up to the late 1950s the goal of potency in the development of novel analgesics was that of the classic opiate morphine. However, in 1957 it was made apparent from reports from CIBA on analgesics based on benzimidazole that levels of activity several orders above this standard could be achieved, and the group is of historical importance on this account.(1,2) The compounds of general formula 3 carry a 2-aminoethyl substituent at N-l and a benzyl substituent at C-2 with further substituents at C-5 and C-4 in the more potent derivatives. Two synthetic routes were employed (Scheme 11.1)<3) (a) condense... 

Sauzem et al. [23] demonstrated that the 5-trifluoromethyl-4,5-dihydro-lH-pyrazole scaffold (xxii) behaves like benzene bioisosteres, supplying novel analgesic and anti-inflammatory pyrazole derivatives. The target pyrazoles were obtained through a rapid one pot cyclocondensation reaction via microwave irradiation. 

Decker MW, Meyer MD. Therapeutic potential of neuronal nicotinic acetylcholine receptor agonists as novel analgesics. 59. Biochem. Pharmacol. 1999 58 917-923. 

Thus it may be quite ethical to compare a novel analgesic against placebo for 2 weeks in the treatment of osteoarthritis of the hip (with escape analgesics available). It would not be ethical to use a placebo alone as comparator in a 6-month trial of a novel drug in active rheumatoid arthritis, even with escape analgesia. 

Oxazolopyridines, such as the novel analgesic (III) now being in clinical trials, constitute a medicinal class of heterocyclic compounds. Phosgenation of 2-amino-3-hydroxy pyridine in the presence of pyridine as scavenger and solvent leads to the oxazolopyridine (I) in excellent yield as shown in scheme 186 (Ref. 238). 

Cevc G, Vierl U, Mazgareanu S (2008) Fimctional characterisation of novel analgesic product based on self-regulating drug carriers. Int J Pharm 360(l-2) 18-28... 

Tamura T, Ogawa J, Taniguchi T, Waki I (1990) Preferential action of eptazocine, a novel analgesic, with opioid receptors in isolated guinea pig ileum and mouse vas deferens preparations. Folia Pharmacol Japon 95 41 16... 

Bentley KW, Hardy DG (1967) Novel analgesics and molecular rearrangements in the morphine-thebaine group. 3. Alcohols of the 6,14-endo-ethenotetrahydrooripavine series and derived analogs of N-allylnormorphine and -norcodeine. J Am Chem Soc 89 3281-3292... 

Ananthan S. Opioid ligands with mixed mu/delta opioid receptor interactions an emerging approach to novel analgesics. AAPS J 2006 8 El 18-25. 

Finally, transgenic FAAH-deficient mice have been developed. They are more responsive to exogenously administered AEA (Cravatt et al. 2001), and their brains contain 15-fold higher levels of AEA than wild-type mice. The phenotype of these mice is characterized also by higher susceptibility to kainate-induced seizures (Clement et al. 2003) and by lower sensitivity to some painful stimuli (Cravatt et al. 2001), which suggests that inhibition of FAAH might lead to the development of novel analgesics. 

Both enantiomers of E-3710 (318), a novel analgesic, were prepared and their absolute stereochemistries assigned their pharmacological properties were compared with those of the racemic and no significant difference was observed <93BMC269). 

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