Twin and Triplet Drugs in Opioid Research

Fujii, H.

doi:10.1007/128_2010_76

Cited by 34 publications

(26 citation statements)

References 154 publications

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“…Moreover, another advantage of hybrid structures is that the can be used to effectively target multifaceted diseases and thus may act not only on one disease but on various co-existing conditions. This is very important because many complex pathologies remain inadequately treated by the commonly used principle of ''one molecule-one target-one disease'' (Decker 2011;Fuji 2011).…”

Section: Discussionmentioning

confidence: 99%

Effects of the Hybridization of Opioid and Neurotensin Pharmacophores on Cell Survival in Rat Organotypic Hippocampal Slice Cultures

et al. 2015

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Several neurotransmitter and neuromodulatory systems can control physiological glutamatergic activity. For example, opioid receptor ligands were shown to partially inhibit N-methyl-D-aspartic acid (NMDA) receptordependent glutamatergic excitotoxicity. Also, the endogenous tridecapeptide neurotensin (NT) was found to modulate excessive glutamate release and glutamate receptor activity in neurons. Alternatively to the one target-one drug approach, it has been well documented that hybrid compounds encompassing two pharmacophores in one molecular scaffold can represent more potent drugs. Moreover, such structures with dual activity can potentially enable a reduction of undesirable side effects and/or improved bioavailability. Herein, we describe the neuroprotective potential of an opioid-NT hybrid peptide (PK20), which was recently designed and synthesized within our group. The protective properties of PK20, assessed in an in vitro model of excitotoxic injury in organotypic hippocampal slice cultures subjected to NMDA, were compared to the effects caused by NT. Our results indicate that PK20 is a potent anti-neurodegenerative agent. Moreover, co-administered with NMDA, PK20 (25-100 ng/ml) dose-dependently reduced hippocampal cell death, determined by a decrease in the propidium iodide signal. We also report for the first time the significant NT-induced neuroprotective effect, as its application (50-100 ng/ml) to hippocampal slice cultures protected CA1 damage against neurotoxicity caused by NMDA.

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Section: Discussionmentioning

confidence: 99%

Effects of the Hybridization of Opioid and Neurotensin Pharmacophores on Cell Survival in Rat Organotypic Hippocampal Slice Cultures

et al. 2015

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“…Twin and triple drugs are defined as compounds that contain two and three pharmacophore components, respectively, exerting pharmacological effects in a one molecule. A twin drug bearing the same pharmacophores is a symmetrical twin drug (homodimer), whereas the one possessing different pharmacophores is a non-symmetrical twin drug (heterodimer) [ 10 , 12 ]. In general, the symmetrical twin drug is expected to produce more potent and/or selective pharmacological effects compared to single molecules, whereas the non-symmetrical twin drug is anticipated to show both pharmacological activities stemming from the individual pharmacophores (dual action) with an additional synergic effect.…”

Section: Structural Conceptsmentioning

confidence: 99%

“…In general, the symmetrical twin drug is expected to produce more potent and/or selective pharmacological effects compared to single molecules, whereas the non-symmetrical twin drug is anticipated to show both pharmacological activities stemming from the individual pharmacophores (dual action) with an additional synergic effect. In a triple drug the two identical portions could bind the same receptor sites simultaneously, while the third portion could bind to a different receptor site or enzyme [ 12 ].…”

Section: Structural Conceptsmentioning

confidence: 99%

Molecular Consortia—Various Structural and Synthetic Concepts for More Effective Therapeutics Synthesis

Pawełczyk

Sowa-Kasprzak

Olender

et al. 2018

IJMS

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The design and discovery of novel drug candidates are the initial and most probably the crucial steps in the drug development process. One of the tasks of medicinal chemistry is to produce new molecules that have a desired biological effect. However, even today the search for new pharmaceuticals is a very complicated process that is hard to rationalize. Literature provides many scientific reports on future prospects of design of potentially useful drugs. Many trends have been proposed for the design of new drugs containing different structures (dimers, heterodimers, heteromers, adducts, associates, complexes, biooligomers, dendrimers, dual-, bivalent-, multifunction drugs and codrugs, identical or non-identical twin drugs, mixed or combo drugs, supramolecular particles and various nanoindividuals. Recently much attention has been paid to different strategies of molecular hybridization. In this paper, various molecular combinations were described e.g., drug–drug or drug-non-drug combinations which are expressed in a schematic multi-factor form called a molecular matrix, consisting of four factors: association mode, connection method, and the number of elements and linkers. One of the most popular trends is to create small–small molecule combinations such as different hybrids, codrugs, drug–drug conjugates (DDCs) and small-large molecule combinations such as antibody-drug conjugates (ADCs), polymer-drug conjugates (PDCs) or different prodrugs and macromolecular therapeutics. A review of the structural possibilities of active framework combinations indicates that a wide range of potentially effective novel-type compounds can be formed. What is particularly important is that new therapeutics can be obtained in fast, efficient, and selective methods using current trends in chemical synthesis and the design of drugs such as the “Lego” concept or rational green approach.

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“…Since opioid peptides are not the only modulators of pain signals in the central nervous system (CNS), a new approach in the search for more efficient analgesics with limited side effects is to combine opioids with other neurotransmitters involved in pain perception (e.g., cholecystokinin, neurotensin, substance P, etc.) [9][10][11][12]. Such novel chimeras, also known as multitarget ligands, may interact independently with their respective receptors and potentially produce more effective antinociception [13].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Pharmacological Evaluation of Hybrids Targeting Opioid and Neurokinin Receptors

Wtorek

Adamska‐Bartłomiejczyk

Piekielna-Ciesielska

et al. 2019

Molecules

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Morphine, which acts through opioid receptors, is one of the most efficient analgesics for the alleviation of severe pain. However, its usefulness is limited by serious side effects, including analgesic tolerance, constipation, and dependence liability. The growing awareness that multifunctional ligands which simultaneously activate two or more targets may produce a more desirable drug profile than selectively targeted compounds has created an opportunity for a new approach to developing more effective medications. Here, in order to better understand the role of the neurokinin system in opioid-induced antinociception, we report the synthesis, structure–activity relationship, and pharmacological characterization of a series of hybrids combining opioid pharmacophores with either substance P (SP) fragments or neurokinin receptor (NK1) antagonist fragments. On the bases of the in vitro biological activities of the hybrids, two analogs, opioid agonist/NK1 antagonist Tyr-[d-Lys-Phe-Phe-Asp]-Asn-d-Trp-Phe-d-Trp-Leu-Nle-NH2 (2) and opioid agonist/NK1 agonist Tyr-[d-Lys-Phe-Phe-Asp]-Gln-Phe-Phe-Gly-Leu-Met-NH2 (4), were selected for in vivo tests. In the writhing test, both hybrids showed significant an antinociceptive effect in mice, while neither of them triggered the development of tolerance, nor did they produce constipation. No statistically significant differences in in vivo activity profiles were observed between opioid/NK1 agonist and opioid/NK1 antagonist hybrids.

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Twin and Triplet Drugs in Opioid Research

Cited by 34 publications

References 154 publications

Effects of the Hybridization of Opioid and Neurotensin Pharmacophores on Cell Survival in Rat Organotypic Hippocampal Slice Cultures

Effects of the Hybridization of Opioid and Neurotensin Pharmacophores on Cell Survival in Rat Organotypic Hippocampal Slice Cultures

Molecular Consortia—Various Structural and Synthetic Concepts for More Effective Therapeutics Synthesis

Synthesis and Pharmacological Evaluation of Hybrids Targeting Opioid and Neurokinin Receptors

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