Abstract
A series of aralkylphenoxyethylamine and aralkylmethoxyphenylpiperazine compounds was synthesized and their in vitro pharmacological profile at both 5-HT(1A) receptors and α(1)-adrenoceptor subtypes was measured by binding assay and functional studies. The results showed that the replacement of the 1,3-dioxolane ring by a tetrahydrofuran, cyclopentanone, or cyclopentanol moiety leads to an overall reduction of in vitro affinity at the α(1)-adrenoceptor while both potency and efficacy were increased at the 5-HT(1A) receptor. A significant improvement of 5-HT(1A)/α(1) selectivity was observed in some of the cyclopentanol derivatives synthesized (4acis, 4ccis and trans). Compounds 2a and 4ccis emerged as novel and interesting 5-HT(1A) receptor antagonist (pK(i) = 8.70) and a 5-HT(1A) receptor partial agonist (pK(i) = 9.25, pD(2) = 9.03, E(max) = 47%, 5-HT(1A)/α(1a) = 69), respectively. Docking studies were performed at support of the biological data and to elucidate the molecular basis for 5-HT(1A) agonism/antagonism activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aorta, Thoracic / drug effects
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Aorta, Thoracic / physiology
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Binding Sites
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CHO Cells
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Cricetinae
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Cricetulus
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Cyclopentanes / chemical synthesis*
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Cyclopentanes / chemistry
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Cyclopentanes / pharmacology
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Drug Partial Agonism
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Furans / chemical synthesis*
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Furans / chemistry
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Furans / pharmacology
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HeLa Cells
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Humans
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In Vitro Techniques
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Ligands
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Male
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Models, Molecular
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Piperazines / chemical synthesis*
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Piperazines / chemistry
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Piperazines / pharmacology
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Radioligand Assay
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Rats
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Receptor, Serotonin, 5-HT1A / metabolism*
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Receptors, Adrenergic, alpha-1 / metabolism*
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Serotonin 5-HT1 Receptor Agonists / chemical synthesis*
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Serotonin 5-HT1 Receptor Agonists / chemistry
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Serotonin 5-HT1 Receptor Agonists / pharmacology
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Serotonin 5-HT1 Receptor Antagonists / chemical synthesis*
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Serotonin 5-HT1 Receptor Antagonists / chemistry
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Serotonin 5-HT1 Receptor Antagonists / pharmacology
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Spleen / drug effects
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Spleen / physiology
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Stereoisomerism
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Structure-Activity Relationship
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Vas Deferens / drug effects
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Vas Deferens / physiology
Substances
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((5,5-diphenyloxolan-2-yl)methyl)(2-phenoxyethyl)amine
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5-((4-(2-methoxyphenyl)piperazin-1-yl)methyl)-2,2-diphenylcyclopentan-1-ol
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Cyclopentanes
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Furans
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Ligands
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Piperazines
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Receptors, Adrenergic, alpha-1
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Serotonin 5-HT1 Receptor Agonists
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Serotonin 5-HT1 Receptor Antagonists
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Receptor, Serotonin, 5-HT1A