TY - JOUR
T1 - Carazolol, an extremely potent β-adrenergic blocker
T2 - Binding to β-receptors in brain membranes
AU - Innis, Robert B.
AU - Corrêa, Fernando M.A.
AU - Snyder, Solomon H.
N1 - Funding Information:
We wish to thank Lynda Heater for expert technical assistance and Billie Little for prepâration of the manuscript . Fernando M. A . Corrêa is the recipient of an international fellowship from Fundacâo de Amparo a Pesquisa do Estado de Sâo Paulo, Brazil, processo biological 77/0627 .
PY - 1979/6/11
Y1 - 1979/6/11
N2 - The binding of (±)-[3H]carazolol, a recently developed β-adrenergic antagonist of high potency, to rat cerebral cortical membranes is compared to the binding of (-)-[3H]dihydroalprenolol (3H-DHA). 3H-Carazolol binds saturably to cortical β-receptors with a KD of 0.15 nM, a value approximately four times lower than that for 3H-DHA. Considering that 3H-carazolol was used as the racemic mixture and 3H-DHA as the (-)-isomer, an equivalent formulation of 3H-carazolol would be 8-10 times more potent than 3H-DHA. This increased affinity can be explained by the observed two fold greater association rate constant and a two fold lower dissociation rate constant. The drug displacement profile of 3H-carazolol binding is very similar to that of 3H-DHA. 3H-Carazolol has equal displacements constants when binding is performed in calf cerebral cortex (which contains mainly β1 receptors) and calf cerebellum (which contains mainly β2 receptors), indicating that 3H-carazolol binds with equal affinity to β1 and β2 receptors. The percent free drug (i.e. unbound to serum proteins) for both carazolol and propranolol in rabbit serum is approximately 10%. At physiologically equivalent doses of carazolol and propranolol in the rabbit, there is no detectable free β-blocking activity at 15, 30 or 60 min after intravenous injection of carazolol, although substantial propranolol activity is detected.
AB - The binding of (±)-[3H]carazolol, a recently developed β-adrenergic antagonist of high potency, to rat cerebral cortical membranes is compared to the binding of (-)-[3H]dihydroalprenolol (3H-DHA). 3H-Carazolol binds saturably to cortical β-receptors with a KD of 0.15 nM, a value approximately four times lower than that for 3H-DHA. Considering that 3H-carazolol was used as the racemic mixture and 3H-DHA as the (-)-isomer, an equivalent formulation of 3H-carazolol would be 8-10 times more potent than 3H-DHA. This increased affinity can be explained by the observed two fold greater association rate constant and a two fold lower dissociation rate constant. The drug displacement profile of 3H-carazolol binding is very similar to that of 3H-DHA. 3H-Carazolol has equal displacements constants when binding is performed in calf cerebral cortex (which contains mainly β1 receptors) and calf cerebellum (which contains mainly β2 receptors), indicating that 3H-carazolol binds with equal affinity to β1 and β2 receptors. The percent free drug (i.e. unbound to serum proteins) for both carazolol and propranolol in rabbit serum is approximately 10%. At physiologically equivalent doses of carazolol and propranolol in the rabbit, there is no detectable free β-blocking activity at 15, 30 or 60 min after intravenous injection of carazolol, although substantial propranolol activity is detected.
UR - http://www.scopus.com/inward/record.url?scp=0018693255&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0018693255&partnerID=8YFLogxK
U2 - 10.1016/0024-3205(79)90102-4
DO - 10.1016/0024-3205(79)90102-4
M3 - Article
C2 - 41147
AN - SCOPUS:0018693255
SN - 0024-3205
VL - 24
SP - 2255
EP - 2264
JO - Life Sciences
JF - Life Sciences
IS - 24
ER -