COMPARISON OF THE INFLUENCE OF N-ISOPROPYL AND N-TERT BUTYL SUBSTITUENTS ON THE AFFINITY OF LIGANDS FOR SINOATRIAL BETA-ADRENOCEPTORS IN RAT ATRIA AND BETA-ADRENOCEPTORS COUPLED TO THE ADENYLYL CYCLASE IN KITTEN VENTRICLE

The potencies as β-adrenoceptor blockers of KL 1006 (the N-isopropyl analogue of bupranolol), pindolol, propranolol and carazolol were compared with potencies of their corresponding tert. butyl analogues bupranolol, tert. butylpindolol, tert. butylpropranol and ter. butylcarazolol. Experiments were carried out at 32.5° C in rat right atria - assessing β-adrenoceptor dependent chronotropic effects - and kitten ventricular membranes - assessing β-adrenoceptor dependent stimulation of adenylyl cyclase - from reserpine pretreated animals. 1. The effects of (-)-isoprenaline on these two systems were antagonized competitively by each of the 8 ligands. 2. None of the 8 ligands caused stimulation or depression of basal adenylyl cyclase activity at concentrations causing antagonism of the effects of (-)-isoprenaline. 3. Pindolol, tert. butylpindolol, carazolol and tert. butylcarazolol were weak partial agonists in rat atria. concentrations of these ligands for producing significant stimulation were higher than those causing significant antagonism of the chronotropic effects of (-)-isoprenaline. 4. Bupranolol, tert. butylpindolol, tert. butylpropranolol and tert. butylcarazolol were 6.6, 3.0, 3.2 and 1.1. times more potent as β-adrenoceptor antagonists in rat atria than their corresponding N-isopropyl analogues, respectively. 5. Bupranolol, tert. butylpindolol, tert. butylpropranolol and tert. butylcarazolol were 4.8, 3.0, 2.7 and 0.6 times more potent as β-adrenoceptor antagonists in kitten membranes than their corresponding N-isopropyl analogues, respectively. 6. The enhanced affinity for myocardial β-adrenoceptors of N-tert. butyl ligands (with respect to the affinity of the corresponding N-isopropyl ligands) appears to be inversely correlated with the size of the ring of the ligands. © 1979 Springer-Verlag.