Opiates structure

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. 

Some side-effects are not particularly serious. Some, in fact, can be advantageous. Euphoria, for example, is a useful side-effect when treating pain in terminally ill patients. Other side-effects, such as constipation, are uncomfortable but can give clues as to other possible uses for opiate-like structures. For example, opiate structures are widely used in cough medicines and the treatment of diarrhoea. 

There is now a search going on for orally active opiate structures which can act as antagonists at the p, receptor, agonists at the k receptor, and have no activity at the a receptor. Some success has been obtained, especially with the compounds shown in Fig. 12.34, but even these compounds still suffer from certain side-effects, or lack the desired oral activity. 

Difenoxin is an opiate, structurally similar to meperidine. It is used as an antidiarrhea]. 

SKIP produces its effects through two classes of GPCR, SRIF-1 and SRIF-2 that are structurally related to cloned opiate receptors. The agonists,... 

In the strict sense, opiates are drugs which are derived from opium and include the natural products morphine, codeine, thebaine and many semi-synthetic congeners derived from them. In the wider sense, opiates are morphine-like drugs with non-peptidic structures. The old term opiates is now more and more replaced by the term opioids which applies to any substance, whether endogenous or synthetic, pqrtidic or non-peptidic, that produces morphine-like effects through an action on opioid receptors. 

The neuroehemical sites for psyehomotor stimulant reward are likely to be the presynaptic dopamine terminals located in the region of the nucleus aeeumbens, frontal cortex, and other forebrain structures that originate in the ventral tegmental area. Note, however, that intraeranial self-administration of eoeaine is elicited from the frontal cortex, but not from the nucleus aeeumbens (Goeders and Smith 1983). Thus, eoneomitant activation of structures other than the nucleus accumbens may be an important part of the circuitry involved in initiation of cocaine intravenous self-administration, as has been hypothesized for the opiates (Smith and Lane 1983 Smith et al. 1982). 

Li, C.H., and Chung, D. Isolation and structure of an untria-kontapeptide with opiate activity from camel pituitary glands. Proc Natl Acad Sci USA 73 1145-1148, 1976. 

Several "sigma opiates," which differ structurally from PCP, are known to induce a PCP-like toxic psychosis, and to displace PCP from rat brain membranes (Zukin 1982 Hampton et al. 1982 ... 

Table 8.2. Structurally similar opiate compounds and their relative potencies.

How similar are natural and synthetic opiates in terms of structure and effects ... 

Structure-Function Analysis of the Cloned Opiate Receptors... 

Changing the amino acid sequence of the cloned receptors by mutating nucleotides within the receptor cDNAs has proven to be an effective mechanism by which to identify structural features of the receptors responsible for their unique functional properties. In particular, site-directed mutagenesis has been employed to determine the ligand binding domains of each opiate receptor. 

Cvejic et al. [133] and Trapaidze et al. [134] have reported that the C-terminus of the 8 receptor is essential for the internalization and downregulation of the receptors. Truncation of the 8 receptor attenuates receptor internalization. Residue Thr353 seems to be selectively involved in the internalization of the receptor, since mutation of this amino acid blocks the internalization process. Recent studies by Chu et al. [135] not only confirm the role of the C-terminus in internalizing the 8 receptor but have shown that clathrin-coated pits are involved in the internalization since a K44I mutant of dynamin I blocks the rapid internalization of the 8 receptor. These studies have identified a structural basis for the differential regulation of the three opiate receptors. 

Blake AD, Bot G, Reisine T. Structure-function analysis of the cloned opiate receptors peptide and small molecule interactions. Chem Biol 1996 3 967-972. 

Sacerdote, P. et al., Antinociceptive and immunosuppressive effects of opiate drugs A structure-related activity study, Hr. J. Pharmacol., 121, no. 4, 834—840, 1997. 

The PE spectra of some other alkaloids like methadone and the opiate narcotics morphine, codeine and heroin have been investigated by Klasinc and coworkers95. Also in this study structure-activity relationships based on IPs were sought but not found. Since the interaction of the drug molecule with the receptor is highly specific, it is not unreasonable that the molecular rather than the electronic structure is more important for the physiological activity. 

A comparable reaction was seen decades ago in the metabolism of methadone [173 - 175]. This well-known synthetic opiate undergoes A-demeth-ylation as a major metabolic reaction in humans and laboratory animals. The resulting secondary amine (11.168, Fig. 11.21) has never been isolated, as it undergoes practically instantaneous cyclization. The reaction is believed to proceed via the carbinolamine with formation of metabolite 11.169 as the major urinary metabolite in humans. This structurally intriguing basic compound is, in its neutral form, a pyrrolidine with an exocyclic C=C bond,... 

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... 

Additional options for refractory disorders include the augmentation of antidepressant treatment with an opiate blocking agent such as naltrexone or consideration of partial or full hospitalization to provide a more structured environment for normalizing the aberrant eating behavior. 

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