Morphine pharmacophore

Fig. 8.3 Space-fining ball-and-s(ick (la-4a, lc-4c) and CPK (lb-4b, ld-4d) three-dimensional molecular models of the structures of morphine (la-ld), methadone (2a-2d), meperidine (3a-3d), and fentanyl (4a-4d). (For two-dimensional structures of morphine, methadone, meperidine, and fentanyl refer to Fig. 8.1). Conventional colors used for different atoms are shown in structures la-4a and lb-4b. In structures Ic- c and ld-4d the morphine pharmacophore of a tertiary alkylamine at least three atoms away from, and including, an aromatic ring is shown in blue while the rest of the molecule is shown in light gray. For methadone, the...

The prototypical opioid is morphine (A.137) (Figure A.39). Isolated in a crude form, called opium, morphine has been recognized as a potent pain killer for thousands of years. Although effective, morphine has a low oral availability (F = 25%). Two common derivatives of morphine include hydrocodone (Vicodin, A.138) and oxycodone (A.139), both of which have oral availabilities of greater than 75%. Oxycodone is often sold in an oral continuous-release form under the trade name of OxyContin. Not all opioids are semisynthetic derivatives of morphine. Dextropropoxyphene (Darvon, A.140) and tramadol (Tramal, A.141) are fully synthetic opioids. Both compounds preserve the pharmacophore of morphine as described in the morphine rule (see Chapter 11). Dextropropoxyphene and tramadol are depicted in Figure A.39 to highlight possible pharmacologically active conformations that resemble morphine. 

Ozonolysis<359) of 6,14-endo-ethenotetrahydrothebaines has afforded aromatic ring cleaved products. Tertiary alcohols (214, R = Me, R1 = alkyl R2 = Me, n-Pr or CBM), for example, gave the lactonic esters 220, which had analgesic potencies similar to that of morphine. This somewhat surprising result suggested that the aromatic pharmacophore in opioids was not an essential feature for a compound to elicit opioid-like responses. The authors(359) indicated that this could be the case if pharmacophores elsewhere in the molecule compensated for the loss of aromatic binding. 

In animal models, these k agonists had potent antinociceptive effects and could eliminate the undesirable side effects of morphine-like drugs. They all had very similar structures that included the N-C-C-Nfv/ 2) pharmacophore sequence (shaded parts in Fig. 4), because they were derived from U-50,488H. Moreover, they lacked the tyrosine moiety that is essential for opioid activity from the viewpoint of endogenous opioid chemistry (Fig. 5). 

D-pharmacophores. TRK-820 is shown in green, and morphine is shown in white. The 3D-pharmacophores of TRK-820 and morphine are represented by dotted and solid spheres, respectively. Matched spheres are indicated by underlined labels... 

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