Analgesic structures, opiate

Problem 28.1 7 Draw the structure of leu-enkephalin, a pentapeptide that acts as an analgesic and opiate, and has... 

Some examples from our recent study of opiate analgesic structures (8,24) serve to illustrate further the types of information which a combined approach can provide. The approach used in this study was 1) accumulate accurate crystal structure results on representative compounds by literature search and performing crystal structure determinations, then 2) develop and verify molecular mechanics potential parameters for use with analgesics, and 3) perform strain energy calculations to find active conformations by comparing different chemical structural types which act at a common receptor. The object of the study was to 1) better define the three-dimensional requirements of opiate analgesics, and 2) better understand the opiate receptor itself by indirectly investigating it. 

Draw the structure of leu-enkephalin, a pentapeptide that acts as an analgesic and opiate, and has the following sequence Tyr-Gly-Gly-Phe-Leu. (The structure of a related peptide, met-enkephalin, appeared in Section 22.6B.)... 

The chemical structures and biological activities of hundreds of opioid analgesics derived from the prototype opioid drug morphine are most comprehensively described in two books published in 1986, one entitled Opioid Analgesics, Chemistry and Receptors by Casy and Parfitt [1] and the other entitled Opiates by Lenz et al. [2]. Follow-up articles include those by Casy in 1989, entitled Opioid Receptors and their Ligands Recent Developments [3] which also includes sections on opioid peptides, affinity labelling and opioid receptor subtypes Rees and Hunter in 1990 [4] covering the... 

The first agent of this class to be introduced in the clinic, haloperidol (18-8), interestingly shares the 4-phenylpiperidine structural fragment found in the central analgesic agent meperidine and its derivatives (see Chapter 7). The former compound may well have been discovered in the course of further SAR studies on the opiate [20]. An unusual synthesis of haloperidol starts with the product (18-1) from Friedel-Crafts acylation of 4-fluorobenzene with succinic anhydride. Successive protection of the... 

Figure 15.2. Structures of opiate analgesics and their antagonists (last five listed).

Among the toxicants that increase respiratory rate are cocaine, amphetamines, and fluoroacetate (all of which are shown in Figure 6.11), nitrites (compounds containing the NOjion), methanol (CH3OH), salicylates, and hexachlorobenzene. Cyanide and carbon monoxide may either increase or decrease respiratory rate. Alcohols other than methanol, analgesics, narcotics, sedatives, phe-nothiazines, and opiates in toxic doses decrease respiratory rate. The structural formulas of some compounds that affect respiratory rate are shown in Figure 6.13. 

Synonyms DM Dextromethorphan hydrobromide Demorphan 3-Methoxy- -methylmorphinan d-Methorphan Drug store wine Robowing Chemical/Pharmaceutical/Other Class The methyl ether of the dextrorotatory form of levor-phanol, an opiate analgesic Chemical Formula C18H25NO Chemical Structure ... 

Chemical/Pharmaceutical/Other Class Opiate analgesic an alkaloid and phenanthrene derivative of opium Chemical Structure ... 

In addition to the inherent difficulties in characterizing the opiate receptor, the problem is compounded by the diversity of chemical structures which are active narcotic analgesics. 

We are now going to look in detail at one of the oldest fields in medicinal chemistry, yet one where true success has proved illusive—the search for a safe, orally active, and non-addictive analgesic based on the opiate structure. 

D. J., Campbell, J.E., Kuntzweiler, T.A., Donnelly-Roberts, D.L., Piattoni-Kaplan, M Briggs, C.A., Williams, M., Arneric, S.P., 1998. Identification and structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors. J. Med. Chem. 41, 407-412. 

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