5-HT1A receptor ligands

Wijngaarden, I. Van; Soudijn, W.; Tulp, M.Th.M.

doi:10.1016/s0165-7208(97)80003-7

Cited by 6 publications

(3 citation statements)

References 66 publications

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“…Among the 5-HT receptors, the 5-HT 1A receptor subtype is the best studied and several classes of agents are known to interact with high affinity. Aminotetralines with 8-OH-DPAT as the most prominent member and arylpiperazines with the spirone class of compounds (e.g., ipsapirone) have been extensively evaluated (Chart ) ergolines, aporphines and aryloxyalkylamines have been investigated .…”

Section: Introductionmentioning

confidence: 99%

“…Aminotetralines with 8-OH-DPAT as the most prominent member and arylpiperazines with the spirone class of compounds (e.g., ipsapirone) have been extensively evaluated (Chart ) ergolines, aporphines and aryloxyalkylamines have been investigated . We entered into the field with the discovery that the indolealkylamine roxindole 1 is not only a dopamine but also a potent 5-HT 1A receptor agonist.…”

Section: Introductionmentioning

confidence: 99%

“…Classic indolealkylamines such as 5-CT show no selectivity for a distinct 5-HT receptor subtype like the endogenous neurotransmitter 5-HT itself. Published efforts to improve selectivity and affinity of derivatives of 5-HT and 5-CT were not successful so far. ,, To elucidate whether it is possible to find compounds in the structural class of roxindole, with selectivity for the 5-HT 1A receptor and devoid of dopamine receptor affinity, we first recall the structural elements responsible for the dopamine receptor interaction.

1 …”

Section: Introductionmentioning

confidence: 99%

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Indolebutylamines as Selective 5-HT_1A Agonists

Heinrich

Böttcher

et al. 2004

J. Med. Chem.

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A series of new 1-[4-(indol-3-yl)butyl]-4-arylpiperazines was prepared to identify highly selective and potent 5-HT(1A) agonists as potential pharmacological tools in studies of mood disorders. The combination of structural elements (indole-alkyl-amine and aryl-piperazine) known to introduce 5-HT(1A) receptor affinity and the proper selection of substituents (R on the indole moiety and R' on the aryl moiety) led to compounds with high receptor specificity and affinity. In particular, the introduction of the methyl ether or the unsubstituted carboxamide as substituents in position 5 of the indole (R) guaranteed serotonergic 5-HT(1A) affinity compared to the unsubstituted analogue. Para-substituted arylpiperazines (R') decreased dopaminergic D(2) binding and increased selectivity for the 5-HT(1A) receptor. Agonistic 5-HT(1A) receptor activity was confirmed in vivo in the ultrasonic vocalization test, and the results suggest that the introduction of the carboxamide residue leads to better bioavailability than the corresponding methyl ether. 3-[4-[4-(4-Carbamoylphenyl)piperazin-1-yl]butyl]-1H-indole-5-carboxamide 54 was identified as a highly selective 5-HT(1A) receptor agonist [GTPgammaS, ED(50) = 4.7 nM] with nanomolar 5-HT(1A) affinity [IC(50) = 0.9 nM] and selectivity [D(2), IC(50) > 850 nM]. 3-[4-[4-(4-Methoxyphenyl)piperazin-1-yl]butyl]-1H-indole-5-carboxamide 45 is one of the most potent and selective 5-HT(1A) agonists known [5-HT(1A), IC(50) = 0.09 nM; D(2), IC(50) = 140 nM].

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

1 …”

Section: Introductionmentioning

confidence: 99%

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Indolebutylamines as Selective 5-HT_1A Agonists

Heinrich

Böttcher

et al. 2004

J. Med. Chem.

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Antidepressants

Iversen¹,

Glennon²

2003

Burger's Medicinal Chemistry and Drug Discovery

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This chapter reviews the 26 antidepressant drugs currently available in Europe and/or the United States from the perspectives of their clinical efficacy, pharmacokinetics, pharmacology, structure‐activity relationships, metabolism, and mechanisms of action. The older nonselective monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine) have largely been replaced by compounds that selectively inhibit monoamine oxidase A (e.g., moclobemide) or by inhibitors of norepinephrine/serotonin monoamine transporter reuptake mechanisms. The first generation of such drugs, the tricyclic antidepressants, suffered from a number of dangerous and unpleasant adverse side effects caused by their many other pharmacological actions on the heart and on cholinergic and other monoamine receptors in the brain. Most of the current generation of antidepressants are serotonin‐selective reuptake inhibitors, which possess a safer side‐effect profile. These drugs have gained widespread use in the treatment of depression and a number of related psychiatric conditions. Some agents that act as norepinephrine‐selective reuptake inhibitors (e.g., reboxetine) are also clinically effective and there is considerable overlap between noradrenergic and serotonergic mechanisms in the CNS. Monoamine selectivity can also be altered by the formation of active metabolites in vivo . All antidepressants require several weeks of treatment before the maximum clinical benefit is seen. This may be attributable to drug‐induced alterations in the expression of receptors in brain (e.g., downregulation of 5‐HT 1A receptors) and/or alterations in the expression of neurotrophic factors (e.g., brain derived neurotrophic factor). New approaches to future antidepressant drug discovery include antagonists for glutamate NMDA receptors, substance P NK1 receptors, or corticotrophin releasing factor receptors.

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Antidepressants

Glennon¹,

Iversen²

2010

Burger's Medicinal Chemistry and Drug Discovery

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This chapter reviews the antidepressant drugs currently available in Europe and/or the United States from the perspectives of their clinical efficacy, pharmacokinetics, pharmacology, structure–activity relationships, metabolism, and mechanisms of action. The older nonselective monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine) have largely been replaced by agents that selectively inhibit monoamine oxidase A (e.g., moclobemide) or by inhibitors of norepinephrine/serotonin monoamine transporter reuptake mechanisms. The first generation of such drugs, the tricyclic antidepressants, suffered from a number of dangerous and unpleasant adverse side effects caused by their many other pharmacological actions on the heart and on cholinergic and other monoamine receptors in the brain. Most of the current generation of antidepressants are serotonin‐selective reuptake inhibitors or mixed norepinephrine/serotonin reuptake inhibitors that possess a safer side‐effect profile. These drugs have gained widespread use in the treatment of depression and a number of related psychiatric conditions, including phobias and the treatment of generalized anxiety disorder (GAD). Some agents that act as norepinephrine‐selective reuptake inhibitors (e.g., reboxetine) are also clinically effective and there is considerable overlap between noradrenergic and serotonergic mechanisms in the CNS. Monoamine selectivity can also be altered by the formation of active metabolites in vivo . All antidepressants require several weeks of treatment before the maximum clinical benefit is seen. This may be attributable to drug‐induced alterations in the expression of receptors in brain (e.g., downregulation of 5‐HT 1A receptors) and/or alterations in the expression of neurotrophic factors (e.g., brain‐derived neurotrophic factor, vascular endothelial growth factor) associated with changes in neurogenesis in certain brain regions. New approaches to future antidepressant drug discovery include antagonists for glutamate NMDA receptors, substance P NK1 receptors, corticotrophin releasing factor receptors, or agonists/antagonists for galanin receptors.

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5-HT1A receptor ligands

Cited by 6 publications

References 66 publications

Indolebutylamines as Selective 5-HT_1A Agonists

Indolebutylamines as Selective 5-HT_1A Agonists

Antidepressants

Antidepressants

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5-HT1A receptor ligands

Cited by 6 publications

References 66 publications

Indolebutylamines as Selective 5-HT1A Agonists

Indolebutylamines as Selective 5-HT1A Agonists

Antidepressants

Antidepressants

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Product

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Indolebutylamines as Selective 5-HT_1A Agonists

Indolebutylamines as Selective 5-HT_1A Agonists