3 - Opioid Receptor Antagonists*

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INTRODUCTION

The pharmacological concept of receptors, based upon the observation of rigid structure-activity relationships, stereospecificity, and the observation of maximal pharmacological responses goes back to the turn of the century. More than a hundred years ago, Fischer [1] proposed the lock-and-key model for the enzyme-glycoside system. Later, Langley [2] and Ehrlich [3] further developed this model which can be applied to receptors as well.

In the early 1950s, the determination of structural

DETERMINATION OF RECEPTOR SELECTIVITY AND ANTAGONISM

Receptor selectivity can be determined using radioligand binding assays. Receptor binding selectivity can be determined by displacement of relatively selective radioligands from receptor sites in membrane suspensions prepared mostly from either rat or guinea-pig brain. Nowadays, cloned μ, κ and δ receptors can be used instead of the brain membrane preparations 21, 22, 23, 24. Recently the GTP-ase assay [24a] and the [35S]GTPγS binding test [24b, 24c] in cell membranes or cloned opioid receptors

UNIVERSAL OPIOID RECEPTOR ANTAGONISTS

Naloxone (1) was the first pure opioid antagonist to be detected and it has become an indispensable tool in opioid research. Both naloxone and its N-cyclopropylmethyl analogue naltrexone (2) are competitive antagonists at μ, κ and δ opioid receptors with some preference for μ receptors. The major criterion for the classification of an agonist effect as being opioid receptor-mediated is the ability of these antagonists to competitively antagonize this effect [26]. The unnatural (+)-isomer of

Competitive antagonists

A series of cyclic conformationally constrained peptides related to somatostatin were designed, synthesized and tested for opioid receptor interaction by Hruby and his collaborators. Compounds (17)-(22) were found to be pure opioid antagonists (GPI) with high affinity (IC50 = 1.2 to 4.3 nM) and exceptional selectivity for μ over δ opioid receptors (Table 3.1) and with minimal or no somatostatin-like activity (ligand binding assays)63, 64, 65.

The peptides (17)-(22) were prepared by the usual

PEPTIDES

Several attempts were made to develop κ selective antagonists through structural modification of dynorphin A. [Ala2,Trp4]dynorphin A-(l–13) has been claimed to be a κ selective opioid antagonist [121], but an accurate opioid receptor binding selectivity profile has not been determined. The three 11-peptide analogues [D-Trp2,8, D-Pro10], [D-Trp58, D-Pro10]- and [D-Trp248, D-Pro 10]-dynorphin A-(l–11) showed weak antagonism against dynorphin A and low κ versus μ selectivity [122]. [N,N

Competitive antagonists

Several δ selective opioid antagonists have been obtained through diallylation of the α-amino group of enkephalin-related peptides [25]. The design of these analogues was based on analogy with the known N-allyl substituted morphinan antagonists. N, N-Diallylated leu-enkephalin (101) was shown to be a moderately potent δ selective antagonist in the MVD [153]. Replacement of the 3,4 position peptide bond in (101) with a thiomethylene moiety resulted in a compound, N,N-diallyl-Tyr-Gly-Glyψ-[CH2

CONCLUSION

In recent years, substantial progress has been made towards the development of opioid receptor antagonists which exhibit high selectivity for μ, κ and δ receptors or receptor subtypes. These highly selective antagonists have advantages over the universal opioid antagonists (for example, naloxone and naltrexone) because they are of value in probing the interaction of endogenous opioid peptides with opioid receptors. They are also useful in evaluating the selectivity of new opioid agonists.

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    This review is dedicated to the memory of the late Drs. Sidney Archer and Hans W. Kosterlitz.

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