Analgesics early development

The development of the first effective analgesic drug, opium, was almost certainly adventitious, and occurred in prehistoric times. The use of the dried exudate from slitting the immature capsule of the opium poppy, Papaver somniferum, as an analgesic, sedative and euphoriant, has a long folkloric history. Isolation of the principal active component morphine (1) as a pure crystalline compound represented one of the early landmarks in organic chemistry. 

One of the early syntheses of meperidine (75) starts with the double alkylation of phenylacetonitrile with the bischloro-ethyl amine, 72. The highly lachrimatory nature of this material led to the development of an alternate synthesis for the intermediate piperidine (73). Alkylation of phenylacetonitrile with two moles of 2-chloroethylvinyl ether leads to the intermediate (69). This is then hydrolyzed without prior isolation to the diol, 70. Treatment with thionyl chloride affords the corresponding dichloro compound (71). This last is then used to effect a bis alkylation on methylamine, in effect forming the piperidine (73) by cyclization at the opposite end from the original scheme. Saponification to the acid (74) followed by esterification with ethanol affords the widely used analgesic meperidine (75) substitution of isopropanol for ethanol in the esterification affords properidine (76). ... 

VAN-H36 (Vita-Invest) is a serotonin and noradrenaline reuptake inhibitor and p-receptor agonist (i.e. has a pharmacological profile of action similar to tramadol). It is in early clinical development as an analgesic. 

By the early nineteenth century, the medicinal use of cannabis spread from Asia and the Middle East to Europe, and finally to the Americas by the mid 1800s. A Western physician named W.B. O Shaughnessey who was working in Calcutta, India, observed the use of cannabis there. After performing tests on animals, the doctor assured himself that cannabis was safe. He developed a solution of cannabis in alcohol, known as a tincture. When placed in the mouth, this tincture proved an effective analgesic (pain reliever). The doctor was also impressed with its muscle relaxant and... 

Dual inhibitors also demonstrate other therapeutical benefits. They reduced the coronary vasoconstriction in arthritic hearts in a rat model [101], and significantly decreased angiotensin II-induced contractions in human internal mammary artery [102], Opioid receptor activation can cause a presynaptic inhibition of neurotransmitter release mediated by LOX metabolites of arachidonic acid in midbrain neurons. The efficacy of opioids was enhanced synergistically by treatment of brain neurons with COX and LOX dual inhibitors. This report might lead to development of CNS analgesic medications involving combinations of lowered doses of opioids and COX/LOX dual inhibitors [103]. The COX and 5-LOX dual inhibitors also can prevent lens protein-induced ocular inflammation in both the early and late phases [104]. 

The focus of this chapter is on recent developments in the opioid field, with summaries of key features of the structure-activity relationships (SAR) of older compounds. Much of the early opioid SAR is discussed in detail in two comprehensive books on opioid analgesics published in 1986 (12, 13). Specific areas in which there has been considerable research in the last decade and which are discussed in this chapter include the molecular biology of opioid receptors (see Section 3.2.4), the design... 

It was later found that the analgesic effect of methopholine rested entirely with the (R)-(-) antipode (150b), in retrospect a better drug (88). The story of methopholine is a classic example of how structure-activity relationships should be resolved early, and the enantiomers studied, before a decision on which compound to be developed is reached. Chlorinated analogs of methopholine were found to have antitussive activity (89), also resting with the (R) isomer. 

One ppm of thiabendazole prevents Ascaris eggs from maturing. In therapeutic topical concentrations, it is used to prevent the development of dog and cat hookworm larvae that have invaded human skin, causing cutaneous larva migrans. In laboratory animals, thiabendazole has antipyretic, analgesic, and antiinflammatory properties, as well as anthelmintic properties. These properties are probably also exhibited in humans and may account for the symptomatic improvement in persons with early systemic trichinosis. 

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