Characterization of propranolol-resistant (-)-[125I]-cyanopindolol binding sites in rat soleus muscle.
1. The characteristics of a propranolol-resistant (-)-[125I]-cyanopindolol (CYP) binding site in rat soleus muscle were determined. 2. Saturation studies performed on homogenates of rat soleus muscle showed two phases of (-)-[125I]-CYP binding, a high affinity site (KD1 30.5 +/- 16.3 pM, Bmax 9.4 +/- 1.38 fmol mg-1 protein) and a lower affinity site (KD2 522.5 +/- 29.1 pM, Bmax 62.19 +/- 11.76 fmol mg-1 protein, n = 4). 3. In rat soleus muscle homogenates labelled with (-)-[125I]-CYP (500 pM), (-)-propranolol competition curves were biphasic with pKD values of 8.30 +/- 0.19, and 5.33 +/- 0.08, n = 7. 4. Competition between (-)-[125I]-CYP (500 pM) and (+/-)-tertatolol, (+/-)-nadolol, (+/-)-alprenolol, (+/-)-CYP, and (-) and (+)-pindolol showed that these compounds competed for binding at the propranolol-resistant site with affinities lower than those displayed at typical beta-adrenoceptors. The atypical beta-adrenoceptor agonists BRL 37344, SR58611A and ICI D7114 and the partial agonist (+/-)-CGP 12177 also competed for (-)-[125I]-CYP binding. 5. Stereoselectivity was demonstrated for the stereoisomers of alprenolol and tertalolol. The (-)-isomers of alprenolol and tertalolol had higher affinity than their corresponding (+)-isomers (3.1 and 2.6 fold respectively). These low stereoselectivity values are a characteristic of atypical beta-adrenoceptors. 6. The beta-adrenoceptor agonists, (-)-adrenaline, (-)-isoprenaline and (-)-noradrenaline, all showed lower affinity than the atypical beta-adrenoceptor agonists and competition curves appeared biphasic in nature. 7. These results confirm the presence of a propranolol-resistant (- )-[125I]-CYP binding site in rat soleus muscle. The affinities of the tested compounds at the propranolol-resistant (- )-[125I]-CYP binding site show similarities to their affinities at 'atypical' beta-adrenoceptors in adipocytes and gastrointestinal tissues and at the cloned beta 3-adrenoceptor.
Roberts
S J
SJ
Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia.
Molenaar
P
P
Summers
R J
RJ
D000318:Adrenergic beta-Agonists / Q000378:metabolism / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D020120:Iodocyanopindolol; D008297:Male; D010869:Pindolol / Q000031:analogs & derivatives* / Q000378:metabolism; D011433:Propranolol / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D007457:Iodine Radioisotopes; D011943:Receptors, Adrenergic, beta; D020120:Iodocyanopindolol; D011433:Propranolol; D010869:Pindolol