Linked Life Data

1674541

Source:http://linkedlifedata.com/resource/pubmed/id/1674541

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
1991-6-26
pubmed:abstractText
Conformational energy calculations using the MM2-87 program have been performed on the tetracyclic spiro amines 1 (A23887) and 2 (A31472) which have previously been shown to have considerable affinity for dopamine D-2 receptors. These compounds are important for defining the pharmacophore for D-2 antagonist activity due to their limited conformational freedom. Possible foldings of the multicyclic structure were energy minimized and the barriers for inversion and for rotation of the ammonium group were computed. The conformational properties of 1 and 2 are consistent with a pharmacophore recently proposed by Liljefors and Bøgesø. The greater affinity of (S)-octoclothepin for D-2 receptors as compared with its enantiomer was attributed to the latter having an incorrect orientation of the ammonium hydrogen despite the correct folding of the tricyclic structure. Other D-2 antagonists with limited conformational freedom such as butaclamol, isobutaclamol, loxapine, clozapine, and resolved cyproheptadine analogues were also found to be consistent with the pharmacophore. In addition, 1, 2, and their enantiomers were tested on radioligand binding assays for dopamine D-1, dopamine D-2, noradrenergic alpha-1, serotonergic 5-HT2, muscarinic, and sigma receptors. 1 and 2 have greater affinities than their enantiomers in the D-1, D-2, alpha-1, and 5-HT2 assays though there was little difference between 2 and its enantiomer in the latter two assays. In the muscarinic assays, 2 and its enantiomer, which were approximately equipotent, had greater affinity than 1 and its enantiomer. None of the compounds had substantial affinity for sigma receptors. Since the same enantiomers of 1, 2, butaclamol, and the resolved cyproheptadine analogues also have greater affinities for D-1 receptors, the conformational requirements of D-1 ligands appear to be quite similar to those of D-2 ligands.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:volume
34
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1707-14
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1991
pubmed:articleTitle
Conformational properties of semirigid antipsychotic drugs: the pharmacophore for dopamine D-2 antagonist activity.
pubmed:affiliation
Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02178.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.