Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
6
|
| pubmed:dateCreated |
1994-1-26
|
| pubmed:abstractText |
With respect to the beta 1- and beta 2-adrenergic receptors (ARs), the beta 3-AR induces specific physiological effects in a few target tissues and exhibits atypical pharmacological properties that distinguish it unambiguously from its counterparts. Therefore, the beta 3-AR represents a suitable model to study the molecular mechanism responsible for receptor subtype selectivity and specificity. Potent beta 3-AR ligands newly characterized in Chinese hamster ovary cells expressing the beta 3-AR were also evaluated in Chinese hamster ovary cells expressing beta 1- and beta 2-ARs and were classified into three groups according to their pharmacological properties. Among the beta 1/beta 2/beta 3 agonists BRL 37344 and LY 79771 exhibit beta 3 selectivity in stimulating adenylyl cyclase; among the beta 1/beta 2 antagonists displaying beta 3 agonistic effects ICI 201651 exhibits beta 3-AR binding selectivity, whereas among the beta 1/beta 2/beta 3 antagonist class bupranolol is the most efficient (but not selective) beta 3-AR antagonist. The structures of these ligands were simulated and compared using computer-generated molecular modeling. Structure-activity relationship analysis indicates that potent or selective beta 3-AR compounds, in addition to possessing a pharmacophore common to all beta-AR ligands, contain a long and bulky alkylamine substituent moiety, which is able to adopt and exchange extended and stacked conformations. Computerized three-dimensional models of the beta 1-, beta 2-, and beta 3-AR binding sites show that more bulky amino acid side chains point inside the groove of the beta 1 and beta 2 sites, compared with the beta 3 site, in a region implicated in signal processing. The long alkylamine chain of compounds behaving as beta 1/beta 2 antagonists and beta 3 agonists may thus adopt either a stacked conformation in the encumbered beta 1- and beta 2-AR sites, leading to antagonistic effects, or an extended conformation in the less encumbered beta 3 site, thus interacting with specific residues implicated in signal transduction.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adrenergic beta-Agonists,
http://linkedlifedata.com/resource/pubmed/chemical/Adrenergic beta-Antagonists,
http://linkedlifedata.com/resource/pubmed/chemical/GTP-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Adrenergic, beta
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Dec
|
| pubmed:issn |
0026-895X
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:volume |
44
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
1094-104
|
| pubmed:dateRevised |
2006-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:7903415-Adrenergic beta-Agonists,
pubmed-meshheading:7903415-Adrenergic beta-Antagonists,
pubmed-meshheading:7903415-Animals,
pubmed-meshheading:7903415-CHO Cells,
pubmed-meshheading:7903415-Cricetinae,
pubmed-meshheading:7903415-GTP-Binding Proteins,
pubmed-meshheading:7903415-Humans,
pubmed-meshheading:7903415-Models, Molecular,
pubmed-meshheading:7903415-Protein Conformation,
pubmed-meshheading:7903415-Receptors, Adrenergic, beta,
pubmed-meshheading:7903415-Signal Transduction,
pubmed-meshheading:7903415-Structure-Activity Relationship
|
| pubmed:year |
1993
|
| pubmed:articleTitle |
Structural and conformational features determining selective signal transduction in the beta 3-adrenergic receptor.
|
| pubmed:affiliation |
Institut Cochin de Génétique Moléculaire, CNRS-UPR 0415, Paris, France.
|
| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|