Bivalent opioid peptide analogues with reduced distances between pharmacophores

doi:10.1016/0024-3205(87)90065-8

Life Sciences

Volume 40, Issue 23, 8 June 1987, Pages 2283-2288

https://doi.org/10.1016/0024-3205(87)90065-8 Get rights and content

Abstract

To investigate the role of distance between two opioid peptide pharmacophores on $in vitro$ and $in vivo$ activities, three new bivalent opioid analogues have been synthesized in which the dipeptide Tyr-D-Phe was connected with diamine moieties (“bridges”). The analogue with a hydrazine bridge has high receptor affinity to mu, kappa, and delta receptor types, as well as potent and long acting antinociceptive activity after intraperitoneal administration.

References (20)

A.W. Lipkowski et al.
Peptides
(1982)
E. Hazum et al.
Biochem. Biophys. Res. Commun.
(1982)
P.S. Portoghese et al.
Life Sci.
(1982)
T. Costa et al.
Biochem. Pharmacol.
(1985)
P.W. Schiller et al.
FEBS Lett.
(1985)
R.A. Lutz et al.
Eur. J. Pharmacol.
(1985)
S.W. Tam
Eur. J. Pharmacol.
(1985)
J.L.K. Hylden et al.
Eur. J. Pharmacol.
(1980)
A.W. Lipkowski et al.

There are more references available in the full text version of this article.

Cited by (55)

The opioid peptide biphalin modulates human corneal epithelial wound healing in vitro
2021, Journal Francais d'Ophtalmologie
Analgesic drugs, including nonselective opioids and non-steroidal anti-inflammatory drugs, should be used with great precautions to relieve pain after trauma to the corneal epithelium because of their unfavorable effects on wound healing. Biphalin is a synthetic opioid peptide that has been demonstrated to possess a strong analgesic effect on rodents. The purpose of this study is to investigate the effects of biphalin on human corneal epithelial wound healing.
An immortalized human corneal epithelial cell (HCEC) culture was used to analyze the effects of biphalin on wound healing. The toxicity of biphalin at various concentrations was measured by the MTT assay. The effects of 1 μM and 10 μM biphalin on wound closure, cell migration and proliferation were tested in an in vitro scratch assay of HCECs. Naloxone, a non-selective competitive opioid receptor antagonist, was also used to inhibit the effects of biphalin in all experiments.
Biphalin did not cause any toxic effect on HCECs at concentrations lower than 100 μM at various incubation time points. Biphalin significantly increased wound healing at 1 μM concentration in an in vitro scratch assay of HCECs (P < 0.05). It also significantly increased migration of HCECs (P < 0.01). There was no significant difference between the biphalin and control groups of HCECs in the Ki67 proliferation assay.
Biphalin, which is a synthetic opioid peptide, promotes corneal epithelial wound healing by increasing cell migration. This role should be evaluated in further in vivo and clinical studies.
Les analgésiques, dont les morphiniques non-sélectifs et les anti-inflammatoires non stéroïdiens (AINS) devraient être utilisés avec beaucoup de précautions pour traiter la douleur dans les lésions de l’épithélium cornéen du fait de leurs effets indésirables sur la cicatrisation. La Biphaline est un peptide morphinique de synthèse dont on a démontré qu’il possède un effet analgésique puissant chez les rongeurs. Le but de cette étude est d’évaluer les effets de la Biphaline sur les lésions de l’épithélium cornéen humain.
Une culture de cellules épithéliales immortalisées de cornée humaine (HCEC) a été utilisée pour tester les effets de la Biphaline sur la cicatrisation. La toxicité de la Biphaline a été mesurée à diverses concentrations par essai MTT. L’effet de 1 μM et de 10 μM de Biphaline ont été testées sur la cicatrisation dans un essai in vitro de grattage de HCEC et séparément de migration et de prolifération cellulaire. La Naloxone, un antagoniste compétitif non sélectif des récepteurs morphiniques, fut aussi utilisée pour inhiber les effets de la Biphaline dans toutes les expériences.
La Biphaline ne produit aucun effet toxique sur les HCEC aux concentrations inférieures à 100 μM aux différents temps d’incubation. La Biphaline augmente significativement la cicatrisation à la concentration de 1 μM dans un test de grattage in vitro d’HCEC (p < 0,05). Elle accroît également significativement la migration des HCEC (p < 0,01). Il n’y a pas de différence significative entre la Biphaline et le groupe témoin de HCEC au test de prolifération Ki67.
La Biphaline, un peptide morphinique de synthèse, favorise la cicatrisation de l’épithélium cornéen par l’augmentation de la migration cellulaire. Ce rôle serait à évaluer par des études in vivo et cliniques ultérieures.
The neuroprotective role of the brain opioid system in stroke injury
2018, Drug Discovery Today
Novel neuroprotective therapies are desperately needed to improve neuronal recovery after ischemic stroke and extend the therapeutic window or offset some of the adverse effects of tissue-type plasminogen activator (tPA). These advances could provide a more effective and safe therapeutic regimen for patients with ischemic stroke. The opioid system has gained intense interest over the past few years and is currently being investigated as a viable target for the pharmacological treatment of stroke. In this review, we focus on different opioid receptors (ORs) and their distribution in the central nervous system (CNS), and the effect of ischemic stroke on their redistribution. We also discuss studies involving the use of the selective and nonselective and/or simultaneous targeting of ORs for neuroprotection during ischemic stroke.
Naloxone exacerbates memory impairments and depressive-like behavior after mild traumatic brain injury (mTBI) in mice with upregulated opioid system activity
2017, Behavioural Brain Research
The neuroprotective role of the endogenous opioid system in the pathophysiological sequelae of brain injury remains largely ambiguous. Noteworthy, almost no data is available on how its genetically determined activity influences the outcome of mild traumatic brain injury. Thus, the aim of our study was to examine the effect of opioid receptor blockage on cognitive impairments produced by mild traumatic brain injury in mice selectively bred for high (HA) and low (LA) swim-stress induced analgesia that show innate divergence in opioid system activity. Mild traumatic brain injury was induced with a weight-drop device on anaesthetized mice. Naloxone (5 mg/kg) was intraperitoneally delivered twice a day for 7 days to non-selectively block opioid receptors. Spatial memory performance and manifestations of depressive-like behavior were assessed using the Morris Water Maze and tail suspension tests, respectively. Mild traumatic brain injury resulted in a significant deterioration of spatial memory performance and severity of depressive-like behavior in the LA mouse line as opposed to HA mice. Opioid receptor blockage with naloxone unmasked cognitive deficits in HA mice but was without effect in the LA line. The results suggest a protective role of genetically predetermined enhanced opioid system activity in suppression of mild brain trauma-induced cognitive impairments. Mice selected for high and low swim stress-induced analgesia might therefore be a useful model to study the involvement of the opioid system in the pathophysiology and neurological outcome of traumatic brain injury.
Biphalin preferentially recruits peripheral opioid receptors to facilitate analgesia in a mouse model of cancer pain - A comparison with morphine
2016, European Journal of Pharmaceutical Sciences
Citation Excerpt :
Moreover, the lack of cross-tolerance to biphalin reported in experiments involving morphine-tolerant DRGs points to the potential relevance of other opioid receptor subtypes (Shen and Crain, 1995). The involvement of κ-opioid receptors was proposed after an observation describing that higher doses of biphalin co-injected with ketamine provoke a slower onset of tolerance in vivo (Kosson et al., 2008; Lipkowski et al., 1987). A similar mechanism was proposed for opioid-induced dependence, where biphalin showed considerably less withdrawal symptoms in rats than morphine (Yamazaki et al., 2001).
The search for new drugs for cancer pain management has been a long-standing goal in basic and clinical research. Classical opioid drugs exert their primary antinociceptive effect upon activating opioid receptors located in the central nervous system. A substantial body of evidence points to the relevance of peripheral opioid receptors as potential targets for cancer pain treatment. Peptides showing limited blood-brain-barrier permeability promote peripheral analgesia in many pain models. In the present study we examined the peripheral and central analgesic effect of intravenously administered biphalin - a dimeric opioid peptide in a mouse skin cancer pain model, developed by an intraplantar inoculation of B16F0 melanoma cells. The effect of biphalin was compared with morphine - a golden standard in cancer pain management. Biphalin produced profound, dose-dependent and naloxone sensitive spinal analgesia. Additionally, the effect in the tumor-bearing paw was largely mediated by peripheral opioid receptors, as it was readily attenuated by the blood-brain-barrier-restricted opioid receptor antagonist - naloxone methiodide. On the contrary, morphine facilitated its analgesic effect primarily by activating spinal opioid receptors. Both drugs induced tolerance in B16F0 - implanted paws after chronic treatment, however biphalin as opposed to morphine, showed little decrease in its activity at the spinal level. Our results indicate that biphalin may be considered a future alternative drug in cancer pain treatment due to an enhanced local analgesic activity as well as lower tolerance liability compared with morphine.
Biphalin protects against cognitive deficits in a mouse model of mild traumatic brain injury (mTBI)
2016, Neuropharmacology
Citation Excerpt :
The neuroprotective action of biphalin seen 7 days after trauma is manifested in behavioral tests as an improvement of cognitive function and on the cellular level by reduction of neuronal damage. Biphalin was primarily designed as a potent nonspecific opioid analgesic that might in the future broaden the choice range of painkilling drugs (Lipkowski et al., 1982, 1987; Horan et al., 1993). Our results confirming the promising neuroprotective effects of biphalin add a new favorable characteristic to the possible first-line treatment of mTBI patients experiencing pain as a result of an accident.
Traumatic brain injury (TBI) is often a result of traffic accidents, contact sports or battlefield explosions. A mild form of traumatic brain injury (mTBI) is frequently underestimated, as the immediate physical symptoms decrease rapidly and conventional neuroimaging studies often do not show visible evidence of brain lesions. However, cognitive impairments persist for weeks, months or even years after the incident. Endogenous opioids were documented to play a role in thmodulation of mTBI pathology, whereas exogenous opioids were shown to possess neuroprotective properties. In the present study, biphalin, a dimeric enkephalin analog, improved cognitive performance in the Morris Water Maze and Novel Object Recognition tests in a mouse weight-drop model of mTBI. The effect of a single systemic injection of 10 mg/kg biphalin immediately after trauma was reversed by naltrexone, suggesting an opioid receptor-mediated mechanism. Biphalin also reduced cortical and hippocampal neurodegeneration, as shown by silver staining. Our data indicates that opioid receptor activation by biphalin may provide neuroprotection of post-traumatic neurodegeneration processes and may protect against memory impairments.
Development and characterisation of novel fentanyl-delta opioid receptor antagonist based bivalent ligands
2015, British Journal of Anaesthesia
Opioid tolerance is a limiting factor in chronic pain. Delta opioid peptide (DOP)(δ) receptor antagonism has been shown to reduce tolerance. Here, the common clinical mu opioid peptide (MOP)(µ) receptor agonist fentanyl has been linked to the DOP antagonist Dmt-Tic (2′,6′-dimethyl-L-tyrosyl-1,2,3,4-tetrahydrisoquinoline-3-carboxylic acid) to create new bivalent compounds.
Binding affinities of bivalents(#9, #10, #11, #12 and #13) were measured in Chinese hamster ovary (CHO) cells expressing recombinant human MOP, DOP, Kappa opioid peptide (KOP)(κ) and nociceptin/orphanin FQ opioid peptide (NOP) receptors. Functional studies, measuring GTPγ[³⁵S] or β-arrestin recruitment, were performed in membranes or whole cells respectively expressing MOP and DOP.
The new bivalents bound to MOP (pK_i : #9:7.31; #10:7.58; #11:7.91; #12:7.94; #13:8.03) and DOP (#9:8.03; #10:8.16; #11:8.17; #12:9.67; #13:9.71). In GTPγ[³⁵S] functional assays, compounds #9(pEC₅₀:6.74; intrinsic activity:0.05) #10(7.13;0.34) and #11(7.52;0.27) showed weak partial agonist activity at MOP. Compounds #12 and #13, with longer linkers, showed no functional activity at MOP. In antagonist assays at MOP, compounds #9 (pK_b:6.87), #10(7.55) #11(7.81) #12(6.91) and #13(7.05) all reversed the effects of fentanyl. At DOP, all compounds showed antagonist affinity (#9:6.85; #10:8.06; #11:8.11; #12:9.42; #13:9.00), reversing the effects of DPDPE ([D-Pen^2,5]enkephalin). In β-arrestin assays, compared with fentanyl (with response at maximum concentration (RMC):13.62), all compounds showed reduced ability to activate β-arrestin (#9 RMC:1.58; #10:2.72; #11:2.40; #12:1.29; #13:1.58). Compared with fentanyl, the intrinsic activity was: #9:0.12; #10:0.20; #11:0.18; #12:0.09 and #13:0.12.
The addition of a linker between fentanyl and Dmt-Tic did not alter the ability to bind to MOP and DOP, however a substantial loss in MOP functional activity was apparent. This highlights the difficulty in multifunctional opioid development.

View all citing articles on Scopus

View full text

Bivalent opioid peptide analogues with reduced distances between pharmacophores

Abstract

Peptides

Biochem. Biophys. Res. Commun.

Life Sci.

Biochem. Pharmacol.

FEBS Lett.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.