Opioid analogues development

As briefly reported the synthesis of an ideal analgesic asks for an improvement of both pharmacodynamic and in pharmacokinetic peculiarities. Sometimes if pharmacodynamic properties are improved, the pharmacokinetic characters can be still far from those of a perfect analgesic molecule. The quantities of opioids normally transported into the CNS can be low, and inadequate blood-brain barrier (BBB) permeation can be responsible for not optimized or for the different analgesic potencies among different opioid analogues. Consistently one major avenue of investigation involves the development of opioid analogues that penetrate the blood-brain-barrier (BBB). 

One major avenue of investigation in the field of opioid agonist and antagonist molecules involves the development of opioid analogues that penetrate the blood-brain-barrier (BBB) In fact inadequate blood-brain barrier (BBB) permeation can be responsible for low analgesic potencies. 

Gentilucci L. New trends in the development of opioid peptide analogues as advanced remedies for pain rehef. Curr Top Med Chem. 2004 4 19-38. 

Schiller PW (1991) Development of receptor-specific opioid peptide analogues. Prog Med Chem 28, 301-340. 

Both peptide and nonpeptide 5-opioid antagonists have been developed. The nonpeptide 6-antagonist naltrindole and its analogues are described in Chapter 9 of this volume. In the present chapter, the development of opioid peptide-derived 6-antagonists, inverse 6-agonists, and mixed p-agonist/6-antagonists is reviewed. 

This dmg, also known as Diprivan, is chemically unlike any of the previously described iv agents and was developed following the discovery of the anesthetic activity of the 2,6-diethyl analogue (111). Propofol itself is insoluble in water and is usually formulated in a soya bean oil emulsion. Propofol induction, with or without an opioid, is smooth and similar to that of other agents, although pain at the injection site and apnea have been reported (112,113). Recovery after induction and maintenance is faster, with fewer side effects, than with thiopentone (114), although sexual disinhibition has been anecdotally reported (115). Propofol is rapidly distributed, metabolized, and eliininated (116). 

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. 

In a pharmacokinetic study, 11 patients taking methadone 35 to 100 mg daily were given efavirenz with two nucleoside analogues. Nine of the patients developed methadone withdrawal symptoms and needed dose increases of 15 to 30 mg (mean 22%). A pharmacokinetic study of these patients found that 3 weeks after starting efavirenz their mean methadone AUCs were reduced by 57% and their maximum plasma levels by 48%. Similar results were found in another study in 5 HIV-positive patients taking methadone 4 patients experienced opioid withdrawal symptoms and a mean methadone dose increase of 52% was required. In another retrospective study, 6 out of 7 patients needed methadone dosage increases of 8% to 200% within 2 weeks to 8 months of starting an efavirenz-based... 

P.W Schiller, Development of Receptor-Specific Opioid Peptide Analogues. In Progress in Medicinal Chemistry, G.P. Ellis and G.B. West, Eds., Elsevier Press, Amsterdam, 1991, pp. 301-340. 

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.

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