Affinity For Opioid Receptors Research Articles

β-Casomorphins: substitution of phenylalanine with β-homo phenylalanine increases the μ-type opioid receptor affinity

Two analogues of bovine β-casomorphin-7 and β-casomorphin-5 containing a β-homo phenylalanine in substitution of the phenylalanine in position 3 were synthesised and tested for their μ-opioid receptor affinity. The modification enhanced the μ receptor affinity 5-fold in the case of modified β-CM-7 and 2-fold for modified β-CM-5 when compared to the natural peptides.

Neuronal inhibitory effects of methadone are predominantly opioid receptor mediated in the rat spinal cord in vivo

This study aims to assess whether the antinociceptive actions of methadone are mediated solely through opioid mechanisms, or whether its reported affinity for NMDA receptors has physiological relevance in vivo. Methadone is a μ-opioid receptor agonist reported to relieve pain unresponsive to other opioids. It is a racemic mixture comprising d - and l -optical isomers; the d -isomer has a lower affinity for opioid receptors, and both also exhibit NMDA receptor binding, likely to indicate antagonist activity. d -Methadone is antinociceptive in behavioural studies via non-opioid mechanisms, which could include functional NMDA receptor-blocking activity. Here we investigate the ability ofd - and dl -methadone to inhibit noxious and innocuous electrically-evoked responses of dorsal horn neurones in the anaesthetized rat.Racemic methadone (5, 25, 50, 250 μg) applied spinally, dose-relatedly inhibited the C-fibre evoked response, input and wind-up of the neurones, with a profile resembling that of morphine. d-Methadone (5, 25, 50, 250, 500 μg) was also inhibitory, although less potent by a factor of between 13 and 48 depending on the neuronal measure; its profile of inhibition resembled that of the racemic mixture rather than an NMDA receptor antagonist. Both compounds had minimal effects on Aβ-fibre-evoked activity. The inhibitory effects of both d - and dl -methadone on noxious-evoked activity were naloxone reversible. The naloxone reversibility of d -methadone inhibitions is best interpreted as indicative of a purely opioid mechanism of action. However, the ability of naloxone to reverse the effects of d -methadone may also reflect a degree of synergy between weak NMDA antagonist and opioid agonist activity. Copyright 2000 European Federation of Chapters of the International Association for the Study of Pain

Opioid activity profiles indicate similarities between the nociceptin/orphanin FQ and opioid receptors

Nociceptin (orphanin FQ) is the recently discovered peptide agonist for the orphan receptor opioid receptor-like 1 (ORL1). Despite the high sequence homology between ORL1 and the opioid receptors, most opioids lack affinity for the nociceptin receptor. The affinity and functional profile of opioids possessing activity at the nociceptin receptor was determined using [ 3H]nociceptin and nociceptin-stimulated [ 35S]GTPγS binding. The μ-opioid receptor-selective agonist lofentanil potently and competitively displaced [ 3H]nociceptin at rat brain receptors (IC 50 62 nM). Lofentanil exhibited full agonism for enhancement of [ 35S]GTPγS binding to human recombinant ORL1 receptors (EC 50 50 nM). The related piperidines ohmefentanyl and sufentanil and the nonselective opioid receptor agonist etorphine were less potent nociceptin receptor agonists. The κ 1+κ 3-opioid receptor agonist/μ-opioid receptor antagonist naloxone benzoylhydrazone was a pure antagonist at both rat brain and human ORL1 receptors. The nonselective opioid receptor partial agonist buprenorphine and the nonselective opioid receptor antagonist (−)-quadazocine exhibited pure antagonism at rat brain receptors, but displayed partial agonism at human ORL1 receptors. Thus, opioids displaying full agonism at the nociceptin receptor are also opioid receptor agonists, whereas opioids that are antagonists or partial agonists at the nociceptin receptor show antagonism or partial agonism at opioid receptors. In addition, the stereospecificity required at opioid receptors appears to be retained at the nociceptin receptor, since (+)-quadazocine is inactive at both receptors. These findings illustrate the structural and functional homology of the opioid recognition site on these two receptor classes and suggest that opioids may provide leads for the design of nonpeptide nociceptin receptor agonists and antagonists lacking affinity for the classical opioid receptors.

Novel Dmt-Tic dipeptide analogues as selective delta-opioid receptor antagonists

A series of Dmt-Tic analogues with substitution on the Tic aromatic ring has been synthesized and evaluated for opioid receptor affinity and activation. Incorporation of large hydrophobic groups at position 7 of Tic did not greatly alter the δ opioid receptor binding affinities of the dipeptides whereas substitution at position 6 substantially diminished their affinity. These modified Dmt-Tic peptides showed binding affinities as low as 2.5 nM with up to 500-fold selectivity for the δ versus μ opioid receptor and proved to be δ receptor antagonists.

Synthesis and opioid receptor affinity of morphinan and benzomorphan derivatives: mixed kappa agonists and mu agonists/antagonists as potential pharmacotherapeutics for cocaine dependence.

This report concerns the synthesis and preliminary pharmacological evaluation of a novel series of kappa agonists related to the morphinan (-)-cyclorphan (3a) and the benzomorphan (-)-cyclazocine (2) as potential agents for the pharmacotherapy of cocaine abuse. Recent evidence suggests that agonists acting at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. We describe the synthesis and chemical characterization of a series of morphinans 3a-c, structural analogues of cyclorphan [(-)-3-hydroxy-N-cyclopropylmethylmorphinan S(+)-mandelate, 3a], the 10-ketomorphinans 4a,b, and the 8-ketobenzomorphan 1b. Binding experiments demonstrated that the cyclobutyl analogue 3b [(-)-3-hydroxy-N-cyclobutylmethylmorphinan S(+)-mandelate, 3b, MCL-101] of cyclorphan (3a) had a high affinity for mu, delta, and kappa opioid receptors in guinea pig brain membranes. Both 3a,b were approximately 2-fold more selective for the kappa receptor than for the mu receptor. However 3b (the cyclobutyl analogue) was 18-fold more selective for the kappa receptor in comparison to the delta receptor, while cyclorphan (3a) had only 4-fold greater affinity for the kappa receptor in comparison to the delta receptor. These findings were confirmed in the antinociceptive tests (tail-flick and acetic acid writhing) in mice, which demonstrated that cyclorphan (3a) produced antinociception that was mediated by the delta receptor while 3b did not produce agonist or antagonist effects at the delta receptor. Both 3a,b had comparable kappa agonist properties. 3a,b had opposing effects at the mu receptor: 3b was a mu agonist whereas 3a was a mu antagonist.

ChemInform Abstract: Preparation and Diastereoselective Birch Reduction—Alkylation of Chiral 3,4‐Dihydro‐1(2H)‐isoquinolinones. Enantiospecific Syntheses and Opioid Receptor Affinities of Several Hydro‐2,3‐dimethyl‐1H‐7,12a‐methanobenzo[6,7]cycloocta [1,2‐c]pyridine‐9‐ols.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Dermorphin and deltorphin glycosylated analogues: synthesis and antinociceptive activity after systemic administration.

In the present paper we describe the synthesis of some dermorphin and deltorphin analogues beta-O- and alpha-C-glycosylated on the C-terminal amino acid residue and report their opioid receptor affinity and selectivity as well as their analgesic potency after subcutaneous injection in mice.

Butorphanol agonist effects and acute physical dependence in opioid abusers: comparison with morphine

This study compared the direct effects and acute physical dependence of butorphanol and morphine, opioids with differing actions at μ versus κ receptors. Six non-dependent heroin-using volunteers were exposed to six conditions in a within-subject, Latin square design using double-blind procedures. In each session, agonist effects of single i.m. injections of butorphanol (3 and 6 mg/70 kg), morphine (15 and 30 mg/70 kg), lorazepam (4 mg/70 kg) or saline were evaluated. Butorphanol and morphine produced effects of comparable magnitude on miosis and reports of `any drug effect'. Volunteers reported dysphoria, confusion and sedation after butorphanol, subjective effects that overlapped with those of lorazepam, whereas morphine produced euphoria and stimulation. Acute physical dependence (i.e. precipitated withdrawal responses to naloxone 10 mg/70 kg i.m. administered 6 h after each treatment) significantly increased after 30 mg/70 kg morphine but not after butorphanol treatments. These differences in naloxone sensitivity are likely due to differences in opioid receptor ( μ versus κ) activity, affinity and efficacy of these compounds. Pharmacological ramifications of these results are discussed.

Buprenorphine alters ethanol self-administration in rats: dose-response and time-dependent effects.

Buprenorphine is a partial opioid agonist derived from thebaine and has high affinity for mu and kappa opioid receptors. The present study investigated dose-response (0.03, 0.15, 0.3, 3 mg/kg) and time-dependent effects of buprenorphine (1.5 or 4 h post-treatment) on EtOH self-administration in outbred Sprague-Dawley rats. Freely feeding and drinking rats were trained to initiate EtOH self-administration for 1 h daily using the ascending concentration procedure, wherein they were provided with increasing concentrations of EtOH at 2, 5, 7, 9 and 11% (v/v), respectively. Water was concurrently available with each concentration. Animals were maintained on a given concentration of EtOH for 5 days. By day 21, animals began their stabilization on the 11% regimen and remained on this concentration throughout the remainder of the study. EtOH and water consumption were recorded daily at both 10- and 60-min intervals. At 1.5 h post-buprenorphine, all test doses greatly suppressed both EtOH and water intake at the 10-min interval. At the 60-min interval, all but the lowest dose (0.03 mg/kg) significantly suppressed EtOH intake, while only the highest dose (3 mg/kg) suppressed water intake. In contrast to the suppressant profile observed at 1.5 h post-buprenorphine, at 4 h post-buprenorphine the lower doses (0.03 and 0.15 mg/kg) significantly increased EtOH intake while the higher doses (0.3 and 3 mg/kg) continued to suppress intake. None of the doses of buprenorphine altered water intake 4 h post-buprenorphine. The results support previous research demonstrating the utility of low doses of buprenorphine in suppressing behavior rewarded by a non-opioid drug.

Design of a high affinity peptidomimetic opioid agonist from peptide pharmacophore models

A pair of diastereomeric peptidomimetics based upon opioid receptor-binding pharmacophore models derived for a series of opioid tetrapeptides was synthesized. Both analogues display high opioid receptor affinity, moderate selectivity for the μ opioid receptor, and are potent, full agonists.

Modified ibogaine fragments: synthesis and preliminary pharmacological characterization of 3-ethyl-5-phenyl-1,2,3,4,5, 6-hexahydroazepino[4,5-b]benzothiophenes.

Five phenyl-substituted derivatives and analogues of 1,2,3,4,5, 6-hexahydroazepino[4,5-b]indole, 5, a major fragment of ibogaine (1), were synthesized and tested for binding to monoamine transporters, the NMDA receptor-coupled cation channel, and dopamine and opioid receptors. All five derivatives, 9 and 17a-d, displayed 8-10-fold higher affinity at the DA transporter than ibogaine and noribogaine (4). At the serotonin transporter, two compounds (9 and 17a) exhibited higher potency than ibogaine, while the rest had weaker binding affinities than the lead compound. In keeping with their structural similarity to ibogaine, all five compounds displayed weak to poor affinity for dopamine D1 and D2 receptors. However, two compounds, 17a,c, demonstrated moderate binding affinities at dopamine D3 receptors. All five compounds displayed weak to poor affinities for mu and kappa opioid receptors and for the NMDA receptor-coupled cation channel. Despite the qualitative differences, derivatives and analogues of 5may serve as useful substitutes for ibogaine.

Slide-binding characterization and autoradiographic localization of delta opioid receptors in rat and mouse brains with the tetrapeptide antagonist [ 3H]TIPP

Slide-binding and autoradiographic studies were performed on cryostat sections from brains of adult Sprague-Dawley rats and BALB C mice to describe the binding characteristics of the tetrapeptide [ 3H]TIPP, an antagonist with high specificity and affinity for the delta opioid receptors. Steady-state binding of [ 3H]TIPP to cryostat sections of brain paste was reached in 120–180 min of incubation. Specific [ 3H]TIPP binding resulted in maximal numbers of binding sites (B max) of 15.59 and 23.91 fmol mg protein, and dissociation constants (K d) of 0.46 and 0.85 nM for rat and mouse brain paste sections, respectively. TIPP displayed the highest affinity for delta opioid receptors in inhibiting specific [ 3H]TIPP binding, with IC 50 values of 0.82 nM and 0.14 nM in rat and mouse brain sections, respectively. While DPDPE was also effective in displacing the specific binding of [ 3H]TIPP (IC 50 = 3.18 ± 0.53 nM and 0.63 ± 0.42 nM in rat and mouse brain paste sections, respectively), other subclass-selective or nonopioid ligands were much less effective, or ineffective. Autoradiographic localization of [ 3H]TIPP binding revealed the characteristic distribution of delta opioid receptors in both species. In consequence of its antagonistic nature, and of its unnatural amino acid residue, which makes this ligand more resistant to biodegradation, [ 3H]TIPP is a superior ligand for evaluation of the binding characteristics and autoradiogaphic distribution of the delta opioid receptors.

Glycodermorphins: opioid peptides with potent and prolonged analgesic activity and enhanced blood-brain barrier penetration.

1. In order to improve the in vivo stability of the opioid peptide dermorphin we synthesized O-betaglucosylated analogs ([Ser7-O-betaGlc]dermorphin and [Ser7-O-betaGlc(Ac)4]-dermorphin) and C-alphagalactosylated analogs ([Ala7-C-alphaGal]dermorphin and [Ala7-C-alphaGal(Ac)4]-dermorphin). 2. O- and C-glycosylation of dermorphin halved the peptide affinity for brain mu-opioid receptors and the biological potency in guinea-pig ileum assay (GPI). Despite their lower opioid receptor affinity, when administered intracerebroventricularly (i.c.v., 8-40 pmol) and subcutaneously (s.c., 0.5-3 micromol kg(-1)) in rats, glycosylated analogs were two times more potent than dermorphin in reducing the nociceptive response to radiant heat. Acetylation of sugar hydroxyl groups reduces 5-10 times both biological activity on GPI and mu-receptor affinity, whereas the antinociceptive potency was equal to (i.c.v.) or only two-three times lower (s.c.) than dermorphin potency. 3. Blood-Brain Barrier Permeability Index (BBB-PI) of the glycodermorphins was significantly higher than that of dermorphin, indicating a facilitated entry into the brain: O-beta-linked glucoconiugates are expected to enter CNS by the glucose transporter GLUT-1 of the endothelial barrier. However the calculated BBB-PI for the C-alphagalactoside was about two times higher than that of the O-betaglucoside, excluding the implication of GLUT-1 that is known to be selective for O-beta-links and preferring for the exose glucose. 4. The enhanced brain permeability with the subsequent decrease in peripheral dosage of these opioid peptides did not result in lowering constipation.

Affinity of Neuropeptide FF Analogs to Opioid Receptors in the Rat Spinal Cord

Several high-affinity analogs of neuropeptide FF (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH 2, NPFF) exhibiting both supraspinal anti-opioid and spinal analgesic activities were studied for their abilities to interact with specific μ, δ, and κ opioid binding in the rat spinal cord. Measurements by quantitative receptor autoradiography in the superficial layers of the spinal cord revealed that NPFF analogs tested have only a low affinity for opioid receptors since K i values ranged from 5 to 400 μ M. Taking into account the high efficacy of NPFF after intrathecal injection, these results indicate that analgesic effects of NPFF did not result from opioid receptor stimulation.

Preclinical enantioselective pharmacology of (R)- and (S)- ketorolac.

Many of the nonsteroidal anti-inflammatory drugs (NSAIDs) are marketed as racemic mixtures, composed of (R)- and (S)- enantiomers. Racemic NSAIDs are potent cyclooxygenase (COX) inhibitors only through the action of the (S)- enantiomers, as the (R)- enantiomers do not exhibit COX inhibition. However, the (R)- enantiomer of ketoprofen exhibits potent analgesic activity and minimal ulcerogenic potential. To extend these observations, we examined the (R)- and (S)- enantiomers of RS- ketorolac, (S)- ketorolac exhibited potent COX1 and COX2 enzyme inhibition, whereas (R)- ketorolac was > 100-fold less active on both COX subtypes. Both enantiomers did not affect norepinephrine or serotonin uptake sites, and nitric oxidase or lipoxygenase activities, nor did they demonstrate any affinity for opioid receptors (mu, delta, or kappa). In experimental models, (S)- ketorolac exhibited about 10-fold greater activity than (R)- ketorolac in the murine phenylquinone writhing model. In this model, morphine sulfate was effective at much lower doses, however, and neither (R)- nor (S)- ketorolac showed any morphine-sparing effect. In the rat gait test for analgesia in the foot paw after injection of brewers yeast suspension, neither (R)- nor (S)- ketorolac affected paw volume. However, both provoked changes in gait scores, the (S)- enantiomer being 30-fold more potent than the (R)- enantiomer. A similar reduction was observed with respect to ulcerogenic potential, measured by direct microscopic changes after test conclusion. These findings suggest that (R)- ketorolac may possess analgesic activity that is independent of COX inhibition and may be associated with reduced ulcerogenic potential compared to effects exhibited by (S)- ketorolac.

Opioid reward mechanisms: a key role in drug abuse?

There is increasing evidence to implicate the mesolimbic dopamine system in the rewarding effects of drugs of abuse such as opioids, psychostimulants, and alcohol, and in addition endogenous opioids may play a key role in the underlying adaptive mechanisms. Opioid agonists with affinity for mu and delta opioid receptors are rewarding, whereas opioid agonists with affinity for kappa receptors are aversive. These opposing motivational effects are paralleled by an increase and decrease, respectively, of dopamine release in the nucleus accumbens. Opposite effects are induced in response to selective antagonists for these different receptor types, pointing to tonically active endogenous opioid reward mechanisms. Withdrawal from chronic morphine results in sensitization for opioid reward; an effect that is counteracted by kappa opioid agonists. The rewarding effects of psychostimulants such as cocaine and amphetamine, mediated by the mesolimbic dopamine pathway, are modulated by opioid mechanisms in both directions: sensitization by morphine pretreatment, inhibition by kappa receptor agonists. A modulatory role of endogenous opioids is also suggested from biochemical data, showing increased dynorphin and kappa receptor expression after chronic cocaine treatment. Alcohol reward involves the mesolimbic reward system also, and opioids modulate this behaviour. Naltrexone as well as selective mu and delta opioid receptor antagonists decrease alcohol consumption in operant conditioning models. Biochemical approaches point to a functional deficit of endogenous opioids in genetic models exhibiting high prevalence for alcohol intake. The therapeutic implications of these data are discussed.

Naltrexone: A case report of pruritus from an antipruritic

Intense, generalized pruritus associated with mycosis fungoides was relieved using subcutaneous naloxone but intensified when changed to the new oral opioid antagonist, naltrexone. Rechallenge again led to worsening in pruritus. This unexpected adverse effect is surprising as naltrexone and naloxone are currently thought to work via similar opioid receptor binding. The worsening of the itch may have been due to adaptation in opioid receptor expression induced by prolonged naloxone therapy, possibly highlighting differential opioid receptor affinity between naltrexone and naloxone, or may have represented an idiosyncratic adverse reaction. Naltrexone and naloxone have been reported to reduce pruritus due to cholestasis, uraemia, morphine epidurals, and possibly atopic dermatitis and urticaria. Naltrexone has the convenience of oral administration and a longer half-life. The role of the opioid system and naltrexone in pruritus is reviewed.

Tritiated deltorphin analogues with high specific radioactivity and high affinity and selectivity for delta opioid receptors

New conformationally constrained deltorphin I and II analogues were designed and synthesized, using a more lipophilic amino acid (Ile) instead of Val at positions 5 and 6, and 2-aminotetralin-2-carboxylic acid (Atc) at position 3. Two analogues (Tyr-D-Ala-(S)-Atc-Asp-Ile-Ile-Gly-NH2 and Tyr-D-Ala-(R)-Atc-Glu-Ile-Ile-Gly-NH2) with high potency and selectivity for δ opioid receptors were chosen for tritiation, with 3,5-I2-Tyr1-deltorphin analogues as precursors. Catalytic dehalotritiation of these precursors resulted in tritiated peptides with high specific radioactivity (1.28 TBq/mmol (34.5 Ci/mmol) and 1.33 TBq/mmol (36.0 Ci/mmol), respectively). © 1997 John Wiley & Sons, Ltd.

Tritiated deltorphin analogues with high specific radioactivity and high affinity and selectivity for delta opioid receptors

Tritiated deltorphin analogues with high specific radioactivity and high affinity and selectivity for delta opioid receptors

Orphanin FQ has an inhibitory effect on the guinea pig ileum and the mouse vas deferens

The activity of the recently isolated endogenous opioid-like peptide orphanin FQ (OFQ) was measured in two classical bioassays of opioid action. OFQ potently and concentration-dependently suppressed the electrically stimulated contractions of the guinea pig ileum (GPI) and the mouse vas deferens (MVD) with EC 50 values of 1.82±0.16 and 2.97±0.01 nM, and E max values of 56±3% and 96±4%, respectively. This effect of OFQ, in both the GPI and MVD, was insensitive to the opioid receptor antagonist naloxone. OFQ competed with [ 3H]diprenorphine binding to μ-, δ- or κ-opioid receptors stably expressed in Chinese hamster ovary cell lines with IC 50 values of 2.1±0.4, 2.2±0.3, 0.75±0.3 μM, respectively. Low affinity for the classical opioid receptors together with the inability of naloxone to antagonize its effect suggest that the inhibitory action of OFQ is mediated via a distinct OFQ receptor in the GPI and MVD. Consequently, the MVD could serve as a valuable bioassay of potential OFQ receptor antagonists.