Development of morphine analogues

Epimerization of a single chiral centre such as the 14-position (Fig. 12.9) is not beneficial either, since changing the stereochemistry at even one chiral centre can result in a drastic change of shape, making it impossible for the molecule to bind to the analgesic receptors. 

To sum up, the important functional groups for analgesic activity in morphine are shown in Fig. 12.10. 

We now move on to consider the development of morphine analogues. As mentioned in Chapter 7, there are several strategies used in drug development. 

We shall consider the following strategies in the development of morphine analogues. 

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Development of morphine tolerance and physical dependence is markedly suppressed by the administration of NTI or its isothiocyanate analogue nal-trindole 5 -isothiocyanate (NTII, 116) before and during morphine treatment [180], These effects are produced by NTI and NTII at doses that do not block the antinociceptive effects due to interaction at fi receptors. These data are of interest from the standpoint of preventing tolerance and physical dependence in patients who receive morphine on a chronic basis [173]. NTI... 

Cyclo(His-D-Leu) acts as a hydrolytic catalyst. Cyclo(Leu-Gly) blocks the development of (1) physical dependence on morphine, (2) tolerance to the pharmacological effects of /3-endorphin, (3) tolerance to haloperidol-induced catalepsy and hypothermia, and (4) dopaminergic supersensitivity after chronic morphine administration. Cyclo(Tyr-Arg), a synthetic analogue of kyortorphin (an endogenous analgesic peptide), and its A-methyl tyrosine derivatives are more potent than kyotorphin in the mouse tail pressure test. ... 

Miosis is a characteristic symptom of opiate administration, and while tolerance develops to many of the pharmacological effects of this class of drugs, tolerance to the miotic effects occurs at a much slower rate. Miosis is due to an excitatory action of the autonomic segment of the nucleus of the oculomotor nerve, an effect attributed to the stimulation of the mu receptors. In general, it would appear that the actions of morphine and its analogues on the brain, spinal cord and gastrointestinal tract are due to stimulation of the mu receptors. 

Biochemical studies of the effects of morphine and its analogues that have been described include the involvement of the central cholinergic system in the effects of morphine withdrawal 187 the effects of administration of reserpine and of amphetamine on the development of tolerance to morphine 188 the possible involvement of vitamin B6 in dependence on morphine 189 the loss of calcium from synaptosomes that is caused by morphine, and its reversal by nalorphine 190 the... 

For a number of years prior to Evans revelations, Rapoport had been involved in the development of a general methodology for the synthesis of several morphine structural analogues. These included both cis and trans 4a-aryldecahydroisoquinolines 127,65 octahydro-lH-benzofuro-[3,2-e]-isoquinolines 128,66 and novel octahydro-lH-[l]-benzopyrano-[4,3,2-e,f]-isoquinolines 129 67... 

Figure 4.5. Structure of hydromorphone, an opioid narcotic. Nearly all opioids bind the p-oplold receptor. There Is no physiological or clinical difference between legal opioids, such as morphine, and illegal ones, such as heroin. In fact, heroin wes thought to be a nonaddic-tive analogue of morphine when it was first developed.

Perhaps it may be possible to use this diversity and selectivity of action to develop new synthetic opiates that will have therapeutic advantages over morphine and its analogues which, in one form or another, have been used by mankind for nearly 2000 years. 

The endogenous peptides methionine and leucine enkephalin (Tyr-Gly-Gly-Phe-Met and Tyr-Gly-Gly-Phe-Leu) are ligands of the opioid receptors. Like the alkaloid morphine, these peptides exhibit significant analgesic effects. As a result, substantial efforts have been applied to develop peptidomimetic analogues of these compounds. 

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