Bivalent opioid peptide analogues with reduced distances between pharmacophores

Lipkowski, A. W.; Konecka, Anna Maria; Sroczyńska, Irmina; Przewlocki, Ryzard; Stala, L.; Tam, S. William

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

Cited by 48 publications

(24 citation statements)

References 13 publications

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“…In addition partial hydrolysis of one active site still leaves another available for receptor interaction. Second, receptor binding studies [6] indicate that biphalin shows good affinity to three types of opioid receptors (/4 6, K) whereas morphine is predominantly a # agonist. If analgesia is mediated by all three receptors then it is plausible that a nonselective but high affinity agonist may possess in vivo potency, especially if multiple receptors act synergistically.…”

Section: Resultsmentioning

confidence: 99%

“…Biphalin (Tyr-D-Ala-Gly-Phe-NH)2 has specific chemical properties that suggest it may have good potential as an analgesic [5]. These incude a structural similarity to the enkephalins, the presence of two active sites linked by a hydrazide bridge [6,7], and a resistance to enzymatic degradation. Analgesic activity has already been demonstrated in the mouse [5] and the rat [8].…”

Section: Introductionmentioning

confidence: 98%

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Analgesic activity of a novel bivalent opioid peptide compared to morphine via different routes of administration

et al. 1991

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A novel bivalent opioid tetrapeptide, biphalin (Tyr-D-Ala-Gly-Phe-NH)2, was synthesized based on structure-activity relationships. The analgesic activity of biphalin was assessed in comparison to morphine in rats. Drugs were administered subcutaneously (s.c.), intravenously (i.v.) and intrathecally (i.t.). Tail flick and tail pinch were used as tests for analgesia. Biphalin s.c. showed negligible analgesic activity, but when given i.v. produced significant analgesia, although less potent than morphine via this route. In contrast, intrathecal biphalin was more potent than morphine. These results indicate that biphalin has intrinsic activity that is compromised by enzymatic degradation or redistribution in the periphery, properties that may render it useful in exploring analgesic actions of locally applied opioids in the periphery without the likelihood of unwanted central effects.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Analgesic activity of a novel bivalent opioid peptide compared to morphine via different routes of administration

et al. 1991

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“…In the present study, we used biphalin, a dimeric peptide [(Tyr-D-Ala-Gly-Phe-NH–)2] in which two enkephalin-type pharmacophores are connected “head-to-head” by a hydrazide bridge [10]. It was shown that biphalin has high affinity to mu opioid receptor (MOP) and delta opioid receptor (DOP) but lower affinity to kappa opioid receptor (KOP) [11, 12]. An antinociceptive character of biphalin was documented in an animal model of cancer pain [13], a semichronic colitis model [14], and in naïve animals [15, 16].…”

Section: Introductionmentioning

confidence: 99%

Biphalin, a Dimeric Enkephalin, Alleviates LPS-Induced Activation in Rat Primary Microglial Cultures in Opioid Receptor-Dependent and Receptor-Independent Manners

et al. 2017

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Neuropathic pain is relatively less responsive to opioids than other types of pain, which is possibly due to a disrupted opioid system partially caused by the profound microglial cell activation that underlines neuroinflammation. We demonstrated that intrathecally injected biphalin, a dimeric enkephalin analog, diminished symptoms of neuropathy in a preclinical model of neuropathic pain in rats (CCI, chronic constriction injury of the sciatic nerve) at day 12 postinjury. Using primary microglial cell cultures, we revealed that biphalin did not influence cell viability but diminished NO production and expression of Iba1 in LPS-stimulated cells. Biphalin also diminished MOP receptor level, as well as pronociceptive mediators (iNOS, IL-1β, and IL-18) in an opioid receptor-dependent manner, and it was correlated with diminished p-NF-κB, p-IκB, p-p38MAPK, and TRIF levels. Biphalin reduced IL-6, IL-10, TNFα, p-STAT3, and p-ERK1/2 and upregulated SOCS3, TLR4, and MyD88; however, this effect was not reversed by naloxone pretreatment. Our study provides evidence that biphalin diminishes neuropathy symptoms, which might be partially related to reduced pronociceptive mediators released by activated microglia. Biphalin may be a putative drug for future pain therapy, especially for the treatment of neuropathic pain, when the lower analgesic effects of morphine are correlated with profound microglial cell activation.

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“…The dimeric analogues were tested for receptor binding to /u, d and x receptors in guinea pig brain homogenates by the methodology identical with that used previously for characterization of other bivalent ligands [9,13]. The K; values are presented in Table II an even more spectacular increase of 40 times for x receptors, while the affinity for d receptors was not significantly affected.…”

Section: Resultsmentioning

confidence: 99%

“…The analo gues exhibited generally high selectivity for < 5 recep tors, and the authors suggested that such dimers could serve as bivalent ligands binding simulta neously to two distinct but closely clustered < 5 recep tors. Lipkowski et al [3,9] have shown that even a shorter bivalent enkephalin analogue with a dihydrazide bond possessed relatively high activity and also <5 receptor selectivity.…”

Section: Introductionmentioning

confidence: 99%

New Dimeric Tetrapeptide Enkephalin AnaloguesHydrophilic Spacer Length and Configuration Affects Potency and Receptor Selectivity

Stępiński

Tam

1994

Zeitschrift Für Naturforschung B

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synthesized and tested in vitro for pi, d and x receptor affinities. They were found to have potent opioid receptor binding activity. The (25,35)-butanediol bridge configuration yield ed selectivity and high potency for pi and x receptors, while the (2/?,37?)-butanediol bridge configuration yielded high potency and selectivity for < 3 receptors. It thus appears that changes in the length and configuration of the polyhydroxyl bridge in dimeric enkephalin analogues can produce a shift in receptor selectivity profiles and therefore suggest the possibility of developing more selective drugs.

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Bivalent opioid peptide analogues with reduced distances between pharmacophores

Cited by 48 publications

References 13 publications

Analgesic activity of a novel bivalent opioid peptide compared to morphine via different routes of administration

Analgesic activity of a novel bivalent opioid peptide compared to morphine via different routes of administration

Biphalin, a Dimeric Enkephalin, Alleviates LPS-Induced Activation in Rat Primary Microglial Cultures in Opioid Receptor-Dependent and Receptor-Independent Manners

New Dimeric Tetrapeptide Enkephalin AnaloguesHydrophilic Spacer Length and Configuration Affects Potency and Receptor Selectivity

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