5-(Sulfonyl)oxy-tryptamines and ethylamino side chain restricted derivatives. Structure–affinity relationships for h5-HT 1B and h5-HT 1D receptors

Barf, Tjeerd; Wikström, Håkan; Pauwels, Petrus J.; Palmier, Christiane; Tardif, Stéphanie; Lundmark, M.; Sundell, Staffan

doi:10.1016/s0968-0896(98)00079-0

Cited by 3 publications

(2 citation statements)

References 24 publications

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“…The corresponding propyl analogue RU 27592 ( 27 , Figure ) was reported by Guillaume et al to be a dopamine antagonist with affinity for both dopamine and 5-HT receptors (80 and 260 nM, respectively) . Other 3-substituted indoles, 1 H -indazoles and 1,2-benzisoxazoles with a piperidine or piperidene ring, and small alkyl groups on the nitrogen have been reported to display effects on serotonin transporter protein (SERT), , as well as on serotonin 5-HT 1D , − 5-HT 1E/1F , 5-HT 1F , , 5-HT 1A/2A , − 5-HT 2A/2C , 5-HT 2A , and 5-HT 6 receptors. − …”

Section: Introductionmentioning

confidence: 97%

Systematic in Vivo Screening of a Series of 1-Propyl-4-arylpiperidines against Dopaminergic and Serotonergic Properties in Rat Brain: A Scaffold-Jumping Approach

Mattsson¹,

Andreasson²,

Waters³

et al. 2012

J. Med. Chem.

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A series of 1-propyl-4-arylpiperidines were synthesized and their effects on the dopaminergic and serotonergic systems tested in vivo and in vitro. Scaffold jumping among five- and six-membered bicyclic aryl rings attached to the piperidine ring had a marked impact on these effects. Potent and selective dopamine D(2) receptor antagonists were generated from 3-indoles, 3-benzoisoxazoles, 3-benzimidazol-2-one, and 3-benzothiophenes. In contrast, 3-benzofuran was a potent and selective inhibitor of monoamine oxidase (MAO) A. The effects of the synthesized compounds on 3,4-dihydroxyphenylacetic acid (DOPAC) levels correlated very well with their affinity for dopamine D(2) receptors and MAO A. In the 4-arylpiperidine series, the most promising compound for development was the 6-chloro-3-(1-propyl-4-piperidyl)-1H-benzimidazol-2-one (19), which displayed typical dopamine D(2) receptor antagonist properties in vivo but produced only a partial reduction on spontaneous locomotor activity. This indicates that the compound may have a lower propensity to induce parkinsonism in patients.

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Section: Introductionmentioning

confidence: 97%

Systematic in Vivo Screening of a Series of 1-Propyl-4-arylpiperidines against Dopaminergic and Serotonergic Properties in Rat Brain: A Scaffold-Jumping Approach

Mattsson¹,

Andreasson²,

Waters³

et al. 2012

J. Med. Chem.

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“…Several applications of the aromatic triflate functionality in medicinal chemistry have recently been presented. − An aromatic triflate group induces less oxidative metabolism in comparison with a hydroxy or methoxy group due to its electron-withdrawing effect and lipophilicity. We reported previously the introduction of the triflate substituent to the intact dibenzodiazepine skeleton of clozapine, aiming at maintaining the interesting pharmacological profile of clozapine while possibly avoiding some aspects of metabolism of clozapine.…”

Section: Introductionmentioning

confidence: 99%

New (Sulfonyloxy)piperazinyldibenzazepines as Potential Atypical Antipsychotics: Chemistry and Pharmacological Evaluation

et al. 1999

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A series of 2- or 8-trifluoromethylsulfonyloxy (TfO) and 2- or 8-methylsulfonyloxy (MsO) 11-piperazinyldibenzodiazepines, -oxazepines, and -thiazepines were synthesized and evaluated in pharmacological models for their potential clozapine-like properties. In receptor binding assays, the 2-TfO analogues (18a, GMC2-83; 24, GMC3-06; and previously reported GMC1-169, 9a) of the dibenzazepines have profiles comparable to that of clozapine, acting on a variety of CNS receptors except they lack M1 receptor affinity. Introduction of 2-TfO to clozapine leads to compound 9e (GMC61-39) which has a similar binding profile as that of clozapine including having M1 receptor affinity. Interestingly, the MsO analogues, as well as the 8-TfO analogues, have no or weak dopaminergic and serotonergic affinities, but all 8-sulfonyloxy analogues do have M1 affinities. In behavioral studies performed to indicate the potential antipsychotic efficacy and the propensity to induce EPS, 2-TfO analogues blocked effectively the apomorphine-induced climbing in mice in a dose-dependent manner with ED50 values (mg/kg) of 2.1 sc for 9a, 1.3 po for 18a, 2.6 sc for 24, and 8.2 sc for 9e. On the other hand, they showed a clear dose separation with regard to their ED50 values (mg/kg) for indicating catalepsy in rats (>44 sc for 9a, 28 po for 18a, 30 sc for 24, and >50 sc for 9e, respectively), thus implicating a more favorable therapeutic ratio (K/A, ED50 climbing/ED50 catalepsy) in comparison with typical neuroleptics such as haloperidol and isoclozapine. Furthermore, compound 18a was also demonstrated to be an orally potent DA antagonist with an ED50 value of 0.7 mg/kg po in the ex vivo L-DOPA accumulation model. The present study contributes to the SAR of 11-piperazinyldibenzazepines, and the 2-TfO analogues of 11-piperazinyldibenzazepines are promising candidates as clozapine-like atypical antipsychotics with low propensity to induce EPS.

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Convenient synthesis of melatonin analogues: 2- and 3-substituted -N-acetylindolylalkylamines

et al. 2004

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5-(Sulfonyl)oxy-tryptamines and ethylamino side chain restricted derivatives. Structure–affinity relationships for h5-HT 1B and h5-HT 1D receptors

Cited by 3 publications

References 24 publications

Systematic in Vivo Screening of a Series of 1-Propyl-4-arylpiperidines against Dopaminergic and Serotonergic Properties in Rat Brain: A Scaffold-Jumping Approach

Systematic in Vivo Screening of a Series of 1-Propyl-4-arylpiperidines against Dopaminergic and Serotonergic Properties in Rat Brain: A Scaffold-Jumping Approach

New (Sulfonyloxy)piperazinyldibenzazepines as Potential Atypical Antipsychotics: Chemistry and Pharmacological Evaluation

Convenient synthesis of melatonin analogues: 2- and 3-substituted -N-acetylindolylalkylamines

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