Pethidine derivatives

The model substance of the prodines is pethidine (meperidine), a centrally active analgesic with the 4-phenylpiperidinecarboxylic acid structure. The prodines are really inverse pethidine derivatives, whose piperidine system is linked by an ester bond to an aliphatic carboxylic acid. Important members of this as yet not very widespread group include MPPP (1-methyl-4-... 

The azacycloheptane (XXX), the most active non-piperidine derivative of the reversed ester series (7 X pethidine), was a typical morphine-like analgesic it... 

Some 1,4-benzodiazepine derivatives, loosely regarded as cyclic versions of basic anilide analgesics, antagonize pethidine in the rat tail-flick test [246]. Activity orders are about 200 times below that of nalorphine for some 4-allyl... 

The 4-phenylpiperidine unit is common to simple piperidine derivatives such as pethidine and a-prodine, and also to morphine, morphinan, and benzomorphan... 

The most known narcotics are the opium alkaloids such as morphine, codeine, thebaine, papaverine, noscapine and their derivatives and modified compounds such as nalmorphine, apomorphine, apomopholcodine, dihydrocodeine, hydro-morphone and heroine, also known as diamorphine. Synthetic narcotics share the structural skeleton of morphine and include dextromethorphan, pentazocine, phenazocine meperidine (pethidine), phentanyl, anfentaitil, remifentalin, methadone, dextropropoxyphene, levoproxyphene, dipipanone, dextromoramide, meptazinol and tramadol. Thebaine derivatives are also modified narcotics and include oxycodone, oxymorphone, etorphine, buprenorphine, nalbuphine, naloxone or naltrexone. Narcotics can be semi-synthesized or totally synthesized from the morphine and thebaine model. The compounds serve various purposes in clinical practise. 

During the late 1930s some 4-phenylpiperidine derivatives were examined as potential spasmolytics on the basis of their chemical relationship to atropine. The antinociceptive properties of one member, ethyl 1-methyl-4-phenyl-piperidine-4-carboxylate, was detected in screening tests and the compound was subsequently introduced into clinical use by Eisleb and Schaumann in 1939. The compound, well known as pethidine in Europe and meperidine in North America (proprietary names include Demerol, Dolantin, and Dolosal), was soon in widespread use for the relief of pain, and it is remarkable how pethidine, the original non-opioid-derived opioid analgesic, has retained its popularity for many years in the face of competition from other synthetic analgesics introduced since 1939. 

An important step for the treatment of severe pain was made in the early 1960s Paul Janssen s exploitation of 4-piperidone chemistry proved remarkably successful in that it led to the clinical use of both a major tranquilizer (haloperidol) and a potent narcotic analgesic, fentanyl. Fentanyl is related to pethidine and also to basic anilides with analgesic properties and is characterized by high potency and short duration of action. Again, a series of derivatives was synthesized over the following decades which led to several products for clinical use, however fentanyl is still very important for the treatment of severe pain. 

Haloperidol (156) and similar butyrophenone derivatives, e.g. droperidol (123), are neuroleptics that were developed from the pethidine series of analgesics. Some (3-aminoketones (Mannich bases) also have neuroleptic activity, an example being molindone (157). 

All drugs derived from opium poppy are called opiates. Of the opiates, heroin (diacetylmorphine) is the most potent and fast-acting. Though heroin is no longer used in medical settings, its less potent cousins— codeine, liquid morphine, pethidine, and methadone— are found in clinics and hospitals all over the world. But it wasn t until the early 1970s that scientists began to understand the real reasons behind heroin s propensity for abuse and addiction. 

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