Homo and Heterodimer Ligands: the Twin Drug Approach

Contreras, Jean‐Marie; Sippl, Wolfgang

doi:10.1016/b978-0-12-374194-3.00018-4

Cited by 37 publications

(27 citation statements)

References 124 publications

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“…1–4 Like mentioned earlier, the combination of two active ligands in a single molecule increases interaction points with its biological target(s), which can lead to a compound with a better on-/off-target profile. 1–4 In addition, we took into consideration, that substitution at position 5 of the pyridine moiety is mostly tolerated for nAChR activity including the possibility of enhancing α4β2* subtype selectivity in contrast to non-substituted analogs. 7 …”

Section: Designmentioning

confidence: 90%

“…1–3 Combining two active compounds in a single molecule increases interaction points with biological target(s) and can provide desired multiple or complementary modes of action. Such compounds are new entities with their own pharmacokinetics and pharmacodynamic properties.…”

Section: Introductionmentioning

confidence: 99%

“…Such compounds are new entities with their own pharmacokinetics and pharmacodynamic properties. 1–4 The combination of two (identical or non-identical) biologically active compounds can be classified by the type of connection: “linker mode” – “no linker mode” – “overlap mode” (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

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The twin drug approach for novel nicotinic acetylcholine receptor ligands

Tomassoli

Gündisch

2015

Bioorganic & Medicinal Chemistry

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The association of two pharmacophoric entities generates so-called “twin drugs” or dimer derivatives. We applied this approach for the design of a small compound library for the interaction with α4β2* nicotinic acetylcholine receptors (nAChRs). In this compound series, the nAChR ligand N,N-dimethyl-2-(pyridin-3-yloxy)ethan-1-amine 9 served as one pharmacological entity and it was initially kept constant as one part of the “twin” compound. “Twin” compounds with identical or non-identical entities using the “no linker mode” or “overlap” mode were synthesized and evaluated for their nAChR affinities. Compound 17a showed the highest affinity for the α4β2* nAChR subtype (Ki = 0.188 nM) and its (di)fluoro analogs could retain nanomolar affinities, when replacing pyridine as the hydrogen bond acceptor system by mono- or difluoro-phenyls. The “twin drug” approach proved to provide compounds with high affinity and subtype selectivity for α4β2* nAChRs.

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Section: Designmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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The twin drug approach for novel nicotinic acetylcholine receptor ligands

Tomassoli

Gündisch

2015

Bioorganic & Medicinal Chemistry

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“…Table 1 presents one of the most common classifications of compounds of this type. By increasing the number of pharmacophores subjected to chemical integration of chemical frameworks, trimeric and higher extended combinations are known in the literature as multitarget drugs or multiple ligands [ 9 , 10 , 11 ]. The most popular and the most frequently reported framework combinations are dual connections, which are completely non-specific structural entities that open up completely new therapeutic perspectives.…”

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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“…In contrast, nonsymmetrical twin drugs may bind to individual relevant binding sites to provide dual actions. 1 To obtain potential drugs with enhanced efficacy or improved safety, drug discovery campaigns have focused on a strategy designing multitarget drugs (DMLs) 2,3 from the viewpoint of polypharmacology. 4 In the opioid field, many twin drugs have been reported.…”

mentioning

confidence: 99%

Synthesis and Pharmacology of a Novel κ Opioid Receptor (KOR) Agonist with a 1,3,5-Trioxazatriquinane Skeleton

Hirayama

Wada

Nemoto

et al. 2014

ACS Med. Chem. Lett.

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We designed and synthesized the 1,3,5-trioxazatriquinane derivatives with m-hydroxyphenyl groups. These compounds include the phenethylamine structure within them, which is a common structure observed in morphinan derivatives like morphine. Among the synthesized compounds, (−)-8c with two m-hydroxyphenyl groups selectively bound and exerted full agonist activity toward the κ opioid receptor (KOR). Subcutaneously administered (−)-8c exhibited significant antinociceptive effects via the KOR in a dose-dependent manner. These results suggest the emergence of a novel class of KOR agonist.

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Homo and Heterodimer Ligands: the Twin Drug Approach

Cited by 37 publications

References 124 publications

The twin drug approach for novel nicotinic acetylcholine receptor ligands

The twin drug approach for novel nicotinic acetylcholine receptor ligands

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

Synthesis and Pharmacology of a Novel κ Opioid Receptor (KOR) Agonist with a 1,3,5-Trioxazatriquinane Skeleton

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