Synthesis and serotonergic activity of arylpiperazide derivatives of serotonin: potent agonists for 5-HT1D receptors

Perez, Michel; Fourrier, Catherine; Sigogneau, I; Pauwels, Petrus J.; Palmier, Christiane; John, Gareth W.; Valentin, Jean‐Pierre; Halazy, S.

doi:10.1021/jm00018a020

Cited by 32 publications

(18 citation statements)

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“…TLC was performed on 5 cmÂ10 cm aluminium plates coated with silice gel 60 F 254 (Merck) in an appropriate solvent. [14][15][16], 1 equiv of 8-9 and 1 equiv of TDAE in anhydrous DMF were stirred at À20 C for 1 h and then warmed up to 70 C for 2 h. b % All yields refer to the chromatographically isolated pure products and are relative to chloride 8-9. a Reaction conditions: 3 equiv of 23, 1 equiv of 8-9 and 1 equiv of TDAE in anhydrous DMF were stirred at À20 C for 1 h and then warmed up to rt for 3 h. b % All yields refer to the chromatographically isolated pure products and are relative to chloride 8-9.…”

Section: Generalmentioning

confidence: 99%

“…General procedure for the reaction of o-and p-nitrobenzyl derivatives 1, 4, 6-9 and a-halocarbonyl derivatives 2a-c 0 , [14][15][16]23 using TDAE. Into a two-necked flask equipped with a nitrogen inlet was added, under nitrogen at À20 C, 6 mL of anhydrous DMF solution of o-and p-nitrobenzyl derivative (2 mmol, 1 equiv) and corresponding a-halocarbonyl derivatives (2a: 2 equiv; 2b: 5 equiv; 2b 0 , 2c, 2c 0 , 14-16, 23: 3 equiv).…”

Section: Procedures For Tdae Reactionmentioning

confidence: 99%

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Original TDAE strategy using α-halocarbonyl derivatives

2009

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Section: Generalmentioning

confidence: 99%

Section: Procedures For Tdae Reactionmentioning

confidence: 99%

Original TDAE strategy using α-halocarbonyl derivatives

2009

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“…This provided us with the rationale for our chemical approach. In taking advantage of the potency and efficacy characteristics of 5-HT compared with tryptamine at 5-HT 1B/1D receptors, F 11356 was synthesized as a novel arylpiperazide 5-HT derivative (22,24) (Fig. 1), which distinguishes F 11356 from the tryptamine derivatives from a chemical point of view.…”

Section: Introductionmentioning

confidence: 99%

Donitriptan, a Unique High‐Efficacy 5‐HT_1B/1D Agonist: Key Features and Acute Antimigraine Potential

et al. 2000

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We hypothesized that the limited acute therapeutic effectiveness of tryptamine derivatives in alleviating migraine headache could be explained by the relatively low intrinsic activity of these agents at 5-HT 1B/1D receptors. Donitriptan is a novel arylpiperazide 5-hydroxytryptamine (5-HT) derivative which was designed to exploit the higher potency and efficacy properties of 5-HT compared to tryptamine at 5-HT 1B/1D receptors.In vitro, donitriptan has subnanomolar affinity for nonhuman and human 5-HT 1B/1D receptors and micromolar affinity for the 5-HTip subtype. Donitritpan potently inhibited forskolin-induced cAMP formation and enhanced specific GTP 35 gS specific binding to a greater extent than tryptamine derivatives and equivalent to 5-HT in C6 cells expressing human 5-HT 1B or 5-HT 1D receptors. Donitriptan produced more potent and larger amplitude increases in hyperpolarizing Ca 2+ -dependent K + current than sumatriptan in guinea pig isolated trigeminal ganglion neurons, and was more potent than tryptamine derivatives in eliciting contractile responses in rabbit isolated saphenous vein rings.In vivo, donitriptan evoked more potent, longer-lasting and greater amplitude carotid vasoconstrictor responses than tryptamine derivatives in anesthetized pigs; and in contrast to sumatriptan, naratriptan or zolmitriptan, produced long-lasting, dose-dependent decreases in unilateral carotid blood flow in conscious dogs at doses from 0.63 mg/kg p.o. without affecting heart rate or behavior. Oral donitriptan also evoked hypothermic responses in guinea pigs suggesting that the compound gains access to the brain.Donitriptan is thus a selective, potent 5-HT 1B/1D receptor agonist which can be distinguished from tryptamine derivatives in consistently exerting high intrinsic activity at these receptors in a series of vascular and neuronal models relevant to migraine. Advantages in terms of therapeutic effectiveness in the acute relief of migraine headache over currently 278 available triptans can be expected to include greater response rates and consistency of pain relief, a lower incidence of migraine recurrence and better tolerability. The acute anti-migraine potential of the first high efficacy 5-HT 1B/1D agonist of its kind, donitriptan, is currently being investigated in man.

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“…During our investigations toward the design and identification of selective 5-HT 1B/1D ligands, we have found that the 5- O -substitution of serotonin with arylpiperazide moieties through a carboxymethyl linker was a very efficient method to design potent, selective, and efficacious 5-HT 1B/1D agonists. − This chemical modification of serotonin (which binds to at least 14 different receptor subtypes) into compounds of general formula 2 is a very efficient way to design selective 5-HT 1B/1D agonists. This observation suggests that 5-HT 1B/1D receptor subtypes possess a deep binding pocket in the binding domain recognizing the substituent attached in the 5- O -position of the serotonin residue.…”

Section: Introductionmentioning

confidence: 99%

5-HT_1B Receptor Antagonist Properties of Novel Arylpiperazide Derivatives of 1-Naphthylpiperazine

et al. 1997

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A new series of arylpiperazide derivatives of 1-naphthylpiperazine of general formula 4 has been prepared and evaluated as 5-HT1B antagonists. Binding experiments at cloned human 5-HT1A, 5-HT1B, and 5-HT1D receptors show that these derivatives are potent and selective ligands for 5-HT1B/1D subtypes with increased binding selectivity versus the 5-HT1A receptor when compared to 1-naphthylpiperazine (1-NP). Studies of inhibition of the forskolin-stimulated cAMP formation mediated by the human 5-HT1B receptor demonstrate that the nature of the arylpiperazide substituent modulates the intrinsic activity of these 1-NP derivatives. Among them, 2-[[8-(4-methylpiperazin-1-yl)naphthalen-2-yl]oxy] -1-(4-o-tolylpiperazin-1-yl)ethanone (4a) was identified as a potent neutral 5-HT1B antagonist able to antagonize the inhibition of 5-HT release induced by 5-CT (5-carbamoyltryptamine) in guinea pig hypothalamus slices. Moreover, 4a was found to potently antagonize the hypothermia induced by a selective 5-HT1B/1D agonist in vivo in the guinea pig following oral administration (ED50 = 0.13 mg/kg).

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Synthesis and serotonergic activity of arylpiperazide derivatives of serotonin: potent agonists for 5-HT1D receptors

Cited by 32 publications

References 2 publications

Original TDAE strategy using α-halocarbonyl derivatives

Original TDAE strategy using α-halocarbonyl derivatives

Donitriptan, a Unique High‐Efficacy 5‐HT_1B/1D Agonist: Key Features and Acute Antimigraine Potential

5-HT_1B Receptor Antagonist Properties of Novel Arylpiperazide Derivatives of 1-Naphthylpiperazine

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Synthesis and serotonergic activity of arylpiperazide derivatives of serotonin: potent agonists for 5-HT1D receptors

Cited by 32 publications

References 2 publications

Original TDAE strategy using α-halocarbonyl derivatives

Original TDAE strategy using α-halocarbonyl derivatives

Donitriptan, a Unique High‐Efficacy 5‐HT1B/1D Agonist: Key Features and Acute Antimigraine Potential

5-HT1B Receptor Antagonist Properties of Novel Arylpiperazide Derivatives of 1-Naphthylpiperazine

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Product

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Donitriptan, a Unique High‐Efficacy 5‐HT_1B/1D Agonist: Key Features and Acute Antimigraine Potential

5-HT_1B Receptor Antagonist Properties of Novel Arylpiperazide Derivatives of 1-Naphthylpiperazine