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Inverse agonism at α2-adrenoceptors in native tissue
- Source :
- European Journal of Pharmacology. 398:185-191
- Publication Year :
- 2000
- Publisher :
- Elsevier BV, 2000.
-
Abstract
- Several alpha(2)-adrenoceptor antagonists have inverse agonist properties in cell culture systems, usually expressing high levels or a constitutively active form of alpha(2)-adrenoceptors. In characterizing the binding of alpha(2)-adrenoceptor agonists to rat brain tissue sections, we found that conditions known to alter agonist affinity for these receptors, particularly the addition of 100 microM GTP, altered the binding of the alpha(2)-adrenoceptor antagonist, [3H](1,4-benzodioxan-2-methoxy-2-yl)-2-imidazoline hydrochloride (RX821002). In further studies, we found that under our conditions [3H]RX821002 demonstrates inverse agonist properties at alpha(2)-adrenoceptors. This is the first demonstration of inverse agonism at alpha(2)-adrenoceptors in native tissue. We found that the alpha(2)-adrenoceptor antagonist, (2S,12bS)1', 3'-dimethylspiro(1,3,4,5',6,6',7,12b-octahydro-2H-benzo(b)fu ro(2, 3-a)quinazoline)-2,4'-pyrimidin-2'-one (MK-912), did not have clearly discernible inverse agonist properties and acted as a neutral antagonist in these studies. On the other hand, the antagonist rauwolscine actually displayed partial agonist properties in our studies. These findings indicate that the inverse agonist properties of alpha(2)-adrenoceptor antagonists can be demonstrated in native tissue, as well as in tissue culture, and they strengthen the idea that inverse agonist properties may be of physiological and pharmacological importance.
- Subjects :
- Agonist
medicine.medical_specialty
medicine.drug_class
Rauwolscine
Biology
Pharmacology
Tritium
Binding, Competitive
Partial agonist
Rats, Sprague-Dawley
Radioligand Assay
chemistry.chemical_compound
Idazoxan
Receptors, Adrenergic, alpha-2
Internal medicine
Adrenergic alpha-2 Receptor Agonists
medicine
Animals
Inverse agonist
Receptor
Adrenergic alpha-Antagonists
Dose-Response Relationship, Drug
Antagonist
Brain
Yohimbine
Adrenergic alpha-2 Receptor Antagonists
Rats
Kinetics
Endocrinology
chemistry
Competitive antagonist
Guanosine Triphosphate
Quinolizines
Endogenous agonist
Protein Binding
Subjects
Details
- ISSN :
- 00142999
- Volume :
- 398
- Database :
- OpenAIRE
- Journal :
- European Journal of Pharmacology
- Accession number :
- edsair.doi.dedup.....3de594ddb83425e0273d192bb5c937ed