Morphine rule

Finally, this general approach produced one of the most potent analgesics known, a compound that paradoxically does not fit the morphine rule at first sight. While details of the preparation are not readily available, in theory at least, treatment... 

Dezocine (30) represents a class of bridged aminotetralins possessing morphine-like analgesic properties. It appears to be roughly equivalent in potency and addiction potential to morphine. The molecule combines molecular features of precedent aminotetralins and benzomor-phans and its structure fits the classical Morphine Rule. The 1-enantiomer is the more active and the p-epimer (equatorial NHj) is the active diastereomer. 

Briefly, the morphine rule suggests that substances... 

A closely related analgesic which does not fit into the morphine rule is nexeridine (73). In this case, 2-phenylcyclohexanone (70) is reacted with... 

A propoxyphene-like analgesic which obeys the empirical morphine rule is pyrroliphene (101). A Mannich reaction involving pyrrolidine, formaldehyde and propiophenone gave amino ketone 99, which was converted to tertiary carbinol 100 by reaction with benzyl magnesium chloride reaction with acetyl... 

Aminonitrile formation on 125 with potassium cyanide and piperidine hydrochloride affords the derivative, 135. Hydrolysis as above gives the corresponding amide (136). Debenzylation is accomplished by catalytic reduction. Alkylation of the secondary amine with the side chain (96) used in the preparation of diphenoxylate affords pirintramide (138) This confound, interestingly enough, is an analgetic agent, although still one that follows the morphine rule, albeit in the side chain. 

Molinazone, 395 Molindone, 455 Monoamine oxidase, 7, 49 Moprolol, 109 Morazone, 261 Morphine, 314 Morphine rule, 17, 328 Moxnidazole, 246... 

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. 

Hundreds of morphine-like molecules have been synthesized and tested for their analgesic properties. Research has shown that not all the complex framework of morphine is necessary for biological activity. According to the morphine rule, biological activity requires (1) an aromatic ring attached to (2) a quaternary carbon atom and (3) a tertiary amine situated (4) two carbon atoms farther away. Meperidine (Demerol), a widely used analgesic, and methadone, a substance used in the treatment of heroin addiction, are two compounds that fit the morphine rule. 

The morphine rule an aromatic rin, attached to a quaternary carhon, attached to two mure carbons, attached to a tertiary amine... 

---