Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
20
pubmed:dateCreated
1999-11-4
pubmed:abstractText
WB 4101 (1)-related benzodioxanes were synthesized by replacing the ethylene chain separating the amine and the phenoxy units of 1 with a cyclopentanol moiety, a feature of 6, 7-dihydro-5-[[(cis-2-hydroxy-trans-3-phenoxycyclopentyl)amino]meth yl] -2-methylbenzo[b]thiophen-4(5H)-one that was reported to display an intriguing selectivity profile at alpha(1)-adrenoreceptors. This synthesis strategy led to 4 out of 16 possible stereoisomers, which were isolated in the case of (-)-3, (+)-3, (-)-4, and (+)-4 and whose absolute configuration was assigned using a chiral building block for the synthesis of (-)-3 starting from (+)-(2R)-2, 3-dihydro-1,4-benzodioxine-2-carboxylic acid ((+)-9) and (1S,2S, 5S)-2-amino-5-phenoxycyclopentan-1-ol ((+)-10). The aim of this project was to further investigate whether it is possible to differentiate between these compounds with respect to their affinity for alpha(1)-adrenoreceptor subtypes and the affinity for 5-HT(1A) receptors, as 1 binds with high affinity at both receptor systems. The biological profiles of reported compounds at alpha(1)-adrenoreceptor subtypes were assessed by functional experiments in isolated rat vas deferens (alpha(1A)), spleen (alpha(1B)), and aorta (alpha(1D)) and by binding assays in CHO and HeLa cells membranes expressing the human cloned alpha(1)-adrenoreceptor subtypes and 5-HT(1A) receptors, respectively. Furthermore, the functional activity of (-)-3, (+)-3, (-)-4, and (+)-4 toward 5-HT(1A) receptors was evaluated by determining the induced stimulation of [(35)S]GTPgammaS binding in cell membranes from HeLa cells transfected with human cloned 5-HT(1A) receptors. The configuration of the cyclopentane unit determined the affinity profile: a 1R configuration, as in (+)-3 and (-)-4, conferred higher affinity at alpha(1)-adrenoreceptors, whereas a 1S configuration, as in (-)-3 and (+)-4, produced higher affinity for 5-HT(1A) receptors. For the enantiomers (+)-4 and (-)-4 also a remarkable selectivity was achieved. Functionally, the stereoisomers displayed a similar alpha(1)-selectivity profile, that is alpha(1D) > alpha(1B) > alpha(1A), which is different from that exhibited by the reference compound 1. The epimers (-)-3 and (+)-4 proved to be agonists at the 5-HT(1A) receptors, with a potency comparable to that of 5-hydroxytryptamine.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
7
pubmed:volume
42
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4214-24
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:10514291-Adrenergic alpha-Agonists, pubmed-meshheading:10514291-Adrenergic alpha-Antagonists, pubmed-meshheading:10514291-Animals, pubmed-meshheading:10514291-Aorta, Thoracic, pubmed-meshheading:10514291-CHO Cells, pubmed-meshheading:10514291-Cloning, Molecular, pubmed-meshheading:10514291-Cricetinae, pubmed-meshheading:10514291-Dioxanes, pubmed-meshheading:10514291-HeLa Cells, pubmed-meshheading:10514291-Humans, pubmed-meshheading:10514291-Male, pubmed-meshheading:10514291-Muscle, Smooth, pubmed-meshheading:10514291-Muscle Contraction, pubmed-meshheading:10514291-Radioligand Assay, pubmed-meshheading:10514291-Rats, pubmed-meshheading:10514291-Rats, Sprague-Dawley, pubmed-meshheading:10514291-Receptors, Adrenergic, alpha-1, pubmed-meshheading:10514291-Receptors, Serotonin, pubmed-meshheading:10514291-Receptors, Serotonin, 5-HT1, pubmed-meshheading:10514291-Serotonin Antagonists, pubmed-meshheading:10514291-Serotonin Receptor Agonists, pubmed-meshheading:10514291-Spleen, pubmed-meshheading:10514291-Stereoisomerism, pubmed-meshheading:10514291-Structure-Activity Relationship, pubmed-meshheading:10514291-Vas Deferens
pubmed:year
1999
pubmed:articleTitle
WB 4101-related compounds. 2. Role of the ethylene chain separating amine and phenoxy units on the affinity for alpha(1)-adrenoreceptor subtypes and 5-HT(1A) receptors.
pubmed:affiliation
Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't