Linked Life Data

10052973

Source:http://linkedlifedata.com/resource/pubmed/id/10052973

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
1999-3-16
pubmed:abstractText
Three series of cycloalkanecarboxylic esters derived from the naturally occurring clavine alkaloids lysergol, dihydrolysergol-I, and elymoclavine were synthesized to study their interaction with 5-HT2A receptors and alpha1-adrenoceptors in rat tail artery and aorta, respectively. Especially cycloalkanecarboxylic esters derived from lysergol showed complex behavior as partial agonists and antagonists of the contractile effect of 5-HT. Within this group, partial 5-HT2A receptor agonist activity was most potent for cyclopropanecarboxylic ester 6a (pKP = 7.67, alpha = 0.21) and decreased as the volume requirement of the alicyclic ring increased. This tendency was echoed in experiments where the compounds were used as antagonists of the contractile effect of 5-HT. From the structure-activity study, the N-1-isopropyl homologue of 6a, compound 6b, emerged as the ligand with the highest affinity for rat 5-HT2A receptors (pA2 = 8.74). For cycloalkanecarboxylic esters derived from dihydrolysergol-I and elymoclavine, no clear structure-affinity relationship could be deduced, although those compounds that had smaller cycloalkyl rings in the acyl portion and an isopropyl substituent at N-1 showed the highest 5-HT2A receptor affinity. On the other hand, cycloalkanecarboxylic esters derived from lysergol, dihydrolysergol-I, and elymoclavine displayed low or marginal affinity at alpha1-adrenoceptors. A further aim of the study was to examine to what extent the complete removal of the acyl portion of the esters would affect 5-HT2A receptor affinity. The parent alcohols of the three series of N-1-isopropyl homologues, 1-isopropyllysergol (1b), 1-isopropyldihydrolysergol-I (2b), and 1-isopropylelymoclavine (3b), displayed higher affinity for 5-HT2A receptors (pA2 = 9.15, 8.50, 9.14) than the corresponding esters. Compounds 1b-3b had no contractile effects by themselves and displayed low affinity at guinea-pig 5-HT1B receptors and rat alpha1-adrenoceptors. The high affinity for rat 5-HT2A receptors was retained when clavines even more simple in structure than 1b-3b, compounds 4b and 5b, were examined as 5-HT2A receptor antagonists. The nanomolar antagonist activity of simple clavines (1b-5b) in the rat suggests that the indolo[4,3-fg]quinoline system of the ergolines is the molecular fragment that is responsible for 5-HT2A receptor affinity, and not the substituent at position C-8.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
25
pubmed:volume
42
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
659-68
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:10052973-Animals, pubmed-meshheading:10052973-Aorta, Thoracic, pubmed-meshheading:10052973-Arteries, pubmed-meshheading:10052973-Ergolines, pubmed-meshheading:10052973-Female, pubmed-meshheading:10052973-Guinea Pigs, pubmed-meshheading:10052973-Iliac Artery, pubmed-meshheading:10052973-Lysergic Acid, pubmed-meshheading:10052973-Male, pubmed-meshheading:10052973-Muscle, Smooth, Vascular, pubmed-meshheading:10052973-Muscle Contraction, pubmed-meshheading:10052973-Rats, pubmed-meshheading:10052973-Rats, Wistar, pubmed-meshheading:10052973-Receptor, Serotonin, 5-HT1B, pubmed-meshheading:10052973-Receptor, Serotonin, 5-HT2A, pubmed-meshheading:10052973-Receptors, Adrenergic, alpha-1, pubmed-meshheading:10052973-Receptors, Serotonin, pubmed-meshheading:10052973-Serotonin Antagonists, pubmed-meshheading:10052973-Serotonin Receptor Agonists, pubmed-meshheading:10052973-Tail
pubmed:year
1999
pubmed:articleTitle
Cycloalkanecarboxylic esters derived from lysergol, dihydrolysergol-I, and elymoclavine as partial agonists and antagonists at rat 5-HT2A receptors: pharmacological evidence that the indolo[4,3-fg]quinoline system of the ergolines is responsible for high 5-HT2A receptor affinity.
pubmed:affiliation
Fachbereich Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2 + 4, D-14195 Berlin (Dahlem), Germany. sieker@schunet.pharmazie.fuberlin-de
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't