Morphine structure-activity relationship

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. 

Even though pure morphine has been available since 1803, its structure was finally elucidated only in 1925, by Sir Robert Robinson. Detailed structure-activity relationships have been worked out during the many years of study of morphine and its derivatives. 

Finally, a considerable number of papers have been devoted to structure-activity relationships in order to find out the essential features for biological activity for instance, analogs of lysergic acid minus one ring, have been synthesized from considerations formally analogous to the modifications of other biologically active molecules such as morphine. The reader is referred to the review article of Campaigne and Knapp (52). 

An examination of the structure-activity relationship (SAR) of a series of enkephalin analogues and morphine derivatives in competing with the binding of radioisotope labeled DADLE and FK 33-824 or opiates revealed that DADLE binds to an opioid receptor selective to Leu-enkephalin and its analogues. In contrast, FK 33-824, morphine, or naloxone binds to opioid receptors with selectivity in favor of morphine and derivatives simi-... 

It has long been known that only morphine and codeine possess analgesic properties, whereas thebaine acts as a convulsant, similar to strychnine [16]. However, analogues produced from thebaine have provided some of the more interesting and clinically useful dmgs such as buprenorphine (see Section 11.5). Indeed, an early structure-activity relationship was realized between morphine and its methylated phenolic relative, codeine. Codeine (see below) is known to have about one-tenth the analgesic activity of morphine, and was also less likely to produce addiction. Additionally, an early diacetylated analogue of morphine, heroin (6) (Fig. 11.2), demonstrated an increased potency but also an increased addictive potential. 

The object of this chapter is to summarize the chemistry of morphine and those pharmacologically interesting related compounds with an intact 4,5-cpoxide bridge. In addition, comment will be made on biological activities and structure-activity relationships (SARs) wherever appropriate. 

Apart from a few notable exceptions (see later), all known narcotic antagonists are based on the morphine, morphinan, or benzomorphan polycyclic systems, that is, on three closely related groups of opioid ligands that share many structure-activity relationships (see Chapters 2, 3, and 4). Details of antagonist representatives of each group will now be given, chiefly confined to N- allyl and N-cyclopropylmethy 1 (CPM) derivatives, with minimal chemical details. 

Analgesics of the 4-arylpiperidine class mimic the geometry of a large portion of morphine when in the axial phenyl chair conformation 33a and were thus earlier believed capable of accommodation at the proposed receptor. This view later fell into disrepute as a result of conformational considerations and particularly the radically different structure-activity relationships in regard to N-substituents and the influence of phenolic hydroxyl between the 4-arylpiperidine and morphine groups. There is evidence that reversed esters of pethidine and other 4-phenylpiperidines with C-4 oxygen functions bind in the equatorial 4-phenyl chair conformation 33b, and receptor modifications necessary to allow uptake of both ax and eq 4-phenyl chairs are discussed... 

The structure-activity relationships of I4-hydroxyinor-phinc derivatives have been reviewed. and several related compounds were. synthesized. - Of these, the dihydrodesoxy compounds possc.s.sed the must analgesic activity. Also, esters of 14-hydroxycodeine derivatives have. shown very high activity. For example, in rats, I4-cinnamyloxycodeinone was I 77 times more active than morphine. 

The Lewis and Husbands group have studied in some detail structure-activity relationships relating to the 14-cinnamoylaminodihydrocodeinones and morphi-nones [37]. In light of the possibility that the delayed morphine antagonism of MC-CAM could be due to its metabolism to C-CAM, a range of alternative phenolic ethers (41) (Fig. 4) of C-CAM were prepared and evaluated [21]. The study showed that, when compared to the methyl ether (41a, MC-CAM), the cyclopropylmethyl... 

With Sertiimer s initial isolation of crystalline material,10 the formidable task of structural elucidation arose. Why did this prove so important a labor The answer of course lies in a consummate desire to separate morphine s equally powerful addictive and analgesic properties. With an established structure in hand, surely in rationalized chemical manipulation of the molecule could one curb its less desirable effects. As a result, morphine may not only be responsible for the birth of alkaloid chemistry, but also the study of structure-activity relationship. 

Holmes, H.L., Structure-Activity Relationships for Some Conjugated Heteraenoid Compounds, Catechol Monoethers and Morphine Alkaloids, (2 vols.), Defence Research Establishment, Suffield, Ralston. Alberta. Canada (1975),... 

The search for new pharmacologically active morphine derivatives continues to produce a voluminous synthetic literature. Part morphine-like compounds (135) and (136) have been prepared. Compound (136) has analgesic properties. A number of homobenzomorphan derivatives have been synthesized in order to probe into structure-activity relationships with respect to their analgesic activity. New dibenzomorphan derivatives have been prepared. ... 

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