Design and synthesis of new potent, silent 5-HT1A antagonists by covalent coupling of aminopropanol derivatives with selective serotonin reuptake inhibitors

Perez, Michel; Pauwels, Petrus J.; Pallard-Sigogneau, I; Fourrier, Catherine; Chopin, Philippe; Palmier, Christiane; Colovray, Véronique; Halazy, S.

doi:10.1016/s0960-894x(98)00619-2

Cited by 21 publications

(19 citation statements)

References 14 publications

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“…Hybrid (or bifunctional ligand) compounds, where two pharmacophores are combined in a single molecule, can be considered an extension of the concept of drug combinations in which the challenges of ensuring compliance with complex regimens or coformulating different compounds into a single tablet can be avoided. Hybrid molecules have been designed for use in various therapeutic areas, such as inflammation (6,16), allergy (2), and depression (20). Typically, two pharmacophores are conjugated through a linker unit, creating a single chemical entity that is able to modulate multiple targets.…”

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confidence: 99%

Design and Evaluation of Primaquine-Artemisinin Hybrids as a Multistage Antimalarial Strategy

Capela

Cabal

Rosenthal

et al. 2011

Antimicrob Agents Chemother

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It is widely accepted that the struggle against malaria depends on the development of new strategies to fight infection. The "magic bullet" thought to be necessary to reach eradication should not only provide treatment for all Plasmodium spp. that infect human red blood cells but should also eliminate the replicative and dormant liver forms of the parasite. Moreover, these goals should ideally be achieved by using different mechanisms of action so as to avoid the development of resistance. To that end, two hybrid molecules with covalently linked primaquine and artemisinin moieties were synthesized, and their effectiveness against the liver and blood stages of infection was compared in vitro and in vivo with those of the parent compounds. Both hybrids displayed enhanced in vitro activities, relative to those of the parent compounds, against Plasmodium berghei liver stages. Both compounds were about as potent as artemisinin against cultured Plasmodium falciparum (50% inhibitory concentration [IC 50 ], ϳ10 nM). When used to treat a murine P. berghei infection, one of the molecules displayed better efficacy than an equimolar mixture of the parent pharmacophores, leading to improved cure and survival rates. These results reveal a novel approach to the design and evaluation of antimalarials based on the covalent combination of molecules acting on different stages of the parasite life cycle.

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confidence: 99%

Design and Evaluation of Primaquine-Artemisinin Hybrids as a Multistage Antimalarial Strategy

Capela

Cabal

Rosenthal

et al. 2011

Antimicrob Agents Chemother

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“…Consequently, there has been considerable interest by several groups to identify drug design strategies focusing on incorporating a 5-HT 1A antagonist component into a 5-HT reuptake inhibitor to bring about a more immediate and complete antidepressant effect [81][82][83][84][85]. Perez et al [81] synthesized several molecules by covalent coupling of known 5-HT 1A antagonists of the aminopropanol family (pindolol, propranolol and penbutolol) with SSRIs like fluoxetine or paroxetine and with the new serotonin noradrenalin reuptake inhibitor antidepressant milnacipram (Fig. 4) [81].…”

Section: Drugs Targeting Serotonin Receptorsmentioning

confidence: 99%

“…Perez et al [81] synthesized several molecules by covalent coupling of known 5-HT 1A antagonists of the aminopropanol family (pindolol, propranolol and penbutolol) with SSRIs like fluoxetine or paroxetine and with the new serotonin noradrenalin reuptake inhibitor antidepressant milnacipram (Fig. 4) [81]. Most of these hybrid molecules were as or even more potent 5-HT 1A antagonists than the parent aminopropranol derivatives, however were found to interact moderately with the 5-HT uptake site [81].…”

Section: Drugs Targeting Serotonin Receptorsmentioning

confidence: 99%

“…4) [81]. Most of these hybrid molecules were as or even more potent 5-HT 1A antagonists than the parent aminopropranol derivatives, however were found to interact moderately with the 5-HT uptake site [81]. Other group focused on modifying a known class of indoles which embrace the known 5-HT uptake inhibitor indalpine.…”

Section: Drugs Targeting Serotonin Receptorsmentioning

confidence: 99%

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Trends in the Development of New Antidepressants. Is there a Light at the End of the Tunnel?

Pacher¹,

Kecskeméti²

2004

CMC

167

104

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Since the introduction of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) in mid-1950's, treatment of depression has been dominated by monoamine hypotheses. The well-established clinical efficacy of TCAs and MAOIs is due, at least in part, to the enhancement of noradrenergic or serotonergic mechanisms, or to both. Unfortunately, their very broad mechanisms of action also include many unwanted effects related to their potent activity on cholinergic, adrenergic and histaminergic receptors.The introduction of selective serotonin reuptake inhibitors (SSRIs) over twenty years ago had been the next major step in the evolution of antidepressants to develop drugs as effective as the TCAs but of higher safety and tolerability profile. During the past two decades SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram) gained incredible popularity and have become the most widely prescribed medication in the psychiatric practice. The evolution of antidepressants continued resulting in introduction of selective and reversible monoamine oxidase inhibitors (eg. moclobemid), selective noradrenaline (eg. reboxetine), dual noradrenaline and serotonin reuptake inhibitors (milnacipram, venlafaxin, duloxetin) and drugs with distinct neurochemical profiles such as mirtazapine, nefazadone and tianeptine. Different novel serotonin receptor ligands have also been intensively investigated. In spite of the remarkable structural diversity, most currently introduced antidepressants are 'monoamine based'. Furthermore, these newer agents are neither more efficacious nor rapid acting than their predecessors and approximately 30% of the population do not respond to current therapies.By the turn of the new millennium, we are all witnessing a result of innovative developmental strategies based on the better understanding of pathophysiology of depressive disorder. Several truly novel concepts have emerged suggesting that the modulation of neuropeptide (substance P, corticotrophin-releasing factor, neuropeptide Y, vasopressin V 1b , melanin-concentrating hormone-1), N-methyl-D-aspartate, nicotinic acetylcholine, dopaminergic, glucocorticoid, δ-opioid, cannabinoid and cytokine receptors, gamma-amino butyric acid (GABA) and intracellular messenger systems, transcription, neuroprotective and neurogenic factors, may provide an entirely new set of potential therapeutic targets, giving hope that further major advances might be anticipated in the treatment of depressive disorder soon.The goal of this review is to give a brief overview of the major advances from monoamine-based treatment strategies, and particularly focus on the new emerging approaches in the treatment of depression.

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“…As proof of concept, co-administration of 5-HT 1A antagonists/partial antagonists and SSRIs has been clinically shown to induce faster antidepressant action than administration of SSRIs alone. 2,3 Recently our laboratories 4-7 and others [8][9][10][11][12][13] have disclosed efforts toward discovering a potentially new class of antidepressant agents based on Ôthe overlapping type approachÕ. This strategy uses a common nitrogen to amalgamate the 5-HT 1A and 5-HT uptake site pharmacophore (Fig.…”

Section: Introductionmentioning

confidence: 99%

Novel aryloxy-8-azabicyclo[3.2.1]oct-3-enes with 5-HT transporter and 5-HT1A affinity

Gilbert

Coleman

Kodah

et al. 2004

Bioorganic & Medicinal Chemistry Letters

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Design and synthesis of new potent, silent 5-HT1A antagonists by covalent coupling of aminopropanol derivatives with selective serotonin reuptake inhibitors

Cited by 21 publications

References 14 publications

Design and Evaluation of Primaquine-Artemisinin Hybrids as a Multistage Antimalarial Strategy

Design and Evaluation of Primaquine-Artemisinin Hybrids as a Multistage Antimalarial Strategy

Trends in the Development of New Antidepressants. Is there a Light at the End of the Tunnel?

Novel aryloxy-8-azabicyclo[3.2.1]oct-3-enes with 5-HT transporter and 5-HT1A affinity

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