3 - Opioid Receptor Antagonists*
Section snippets
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-Trp5’8, D-Pro10]- and [D-Trp2’4’8, 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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2024, Asian Journal of PsychiatryEffect of combination of peripheral oxytocin and naltrexone at subthreshold doses on food intake, body weight and feeding-related brain gene expression in male rats
2021, Physiology and BehaviorCitation Excerpt :In a recent human case study involving an adolescent male with hypothalamic obesity and uncontrollable food-seeking caused by craniopharyngioma resection, Hsu et al. administered OT to decrease energy intake and body weight [13]. After 10 weeks of OT administration, considering suboptimal effectiveness of OT on eating for reward, they began co-administering OT with naltrexone (NTX), a non-selective opioid receptor antagonist [21], thereby capitalizing on the primary effect of opioid receptor blockade on diminishing reward-driven consumption [22-24]. While OT alone reduced body weight and hyperphagia during the first weeks, co-administration with NTX was a successful adjunctive therapy leading to further improvements in body weight and satiety parameters.
Binding mode analyses of NAP derivatives as mu opioid receptor selective ligands through docking studies and molecular dynamics simulation
2017, Bioorganic and Medicinal ChemistryCitation Excerpt :Their crystal structures have been reported recently,8–14 which allow us to study their structural characteristics at the atomic level. Moreover, MOR, KOR, and DOR are also involved in many common physiological processes, such as pain perception, depression, anxiety, and drug abuse and addiction.15–18 It has been demonstrated that the MOR plays primary role in controlling antinociception, and the DOR is linked to mood related disorders,19,20 while the KOR is known to cause dysphoric effects as well as anxiety.21–23
Binding mode characterization of 6α- and 6β-N-heterocyclic substituted naltrexamine derivatives via docking in opioid receptor crystal structures and site-directed mutagenesis studies: Application of the 'message-address' concept in development of mu opioid receptor selective antagonists
2013, Bioorganic and Medicinal ChemistryCitation Excerpt :Because receptor-selective opioid antagonists are vital tools for identifying the receptor types involved in interactions with selective opioid agonists, such antagonists have played very important roles in the study of opioid receptors. In general, an agonist interaction is characterized as opioid receptor-mediated only if its effect is competitively inhibited by an opioid antagonist.1–3 More specifically, characterization of the mu opioid receptor (MOR) structure–function relationship is essential because the analgesic effect, addictive properties, and notorious side effects (such as addiction/abuse liability, respiratory depression, and constipation) of the key drug morphine are abolished in MOR knock-out mice, indicating that these side effects are primarily due to its interaction with the MOR.4–6
Opioid receptor selectivity profile change via isosterism for 14-O-substituted naltrexone derivatives
2013, Bioorganic and Medicinal Chemistry LettersEffect of non-dopaminergic drug treatment on Levodopa induced dyskinesias in MPTP monkeys: Common implication of striatal neuropeptides
2010, NeuropharmacologyCitation Excerpt :Chronic opioid antagonist treatment induces hypersensitivity and upregulation of opioid receptors (Lesscher et al., 2003). Since naltrexone is an opioid antagonist with a long duration of action (Schmidhammer, 1998), modulation of motor responses could be related to the non-selective antagonistic effect of naltrexone and high levels of striatal neuropeptides could play a role to compensate long-term adaptive changes that are responsible for the induction of dyskinesias rather than be the cause of them. A better understanding of opioidergic signaling in the basal ganglia and development of drugs that selectively target μ, δ and κ opioid peptide receptors or opioid antagonists/partial agonists could provide new ways to treat the involuntary movements induced by L-DOPA.
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This review is dedicated to the memory of the late Drs. Sidney Archer and Hans W. Kosterlitz.