TY - JOUR
T1 - Ionization and surface properties of verapamil and several verapamil analogues
AU - Retzinger, G. S.
AU - Cohen, L.
AU - Lau, S. H.
AU - Kézdy, F. J.
PY - 1986/10
Y1 - 1986/10
N2 - We have investigated the ionization and surface properties of verapamil (5‐[(3, 4‐dimethoxyphenethyl)methylamino]‐2‐(3, 4‐dimethoxyphenyl)‐2‐isopropylvaleronitrile, 1) and several verapamil analogues since these properties appear to be involved in the biologic activities of these compounds. Our results show that verapamil and its analogues are surface‐active and bind to amphiphilic surfaces. The affinity toward, as well as the capacity of, an amphiphilic surface for verapamil and its ionizable analogues is pH dependent, with the surface having both higher affinity and capacity for the neutral form of the molecules. Thus, verapamil exists as protonated and neutral forms, both of which are free in solution and adsorbed to the interface, and the ionization of verapamil at an interface changes with respect to its ionization in solution. From analyses of the pH dependency of surface binding and of solution and interfacial ionizations, we determined the values of the four equilibrium constants. These equilibrium constants permit correlative studies between the pH‐dependent abundance of each species and biologic activity. We discuss preliminary studies which indicate that the negative inotropic effect of verapamil is mediated by the membrane‐bound neutral form of the drug.
AB - We have investigated the ionization and surface properties of verapamil (5‐[(3, 4‐dimethoxyphenethyl)methylamino]‐2‐(3, 4‐dimethoxyphenyl)‐2‐isopropylvaleronitrile, 1) and several verapamil analogues since these properties appear to be involved in the biologic activities of these compounds. Our results show that verapamil and its analogues are surface‐active and bind to amphiphilic surfaces. The affinity toward, as well as the capacity of, an amphiphilic surface for verapamil and its ionizable analogues is pH dependent, with the surface having both higher affinity and capacity for the neutral form of the molecules. Thus, verapamil exists as protonated and neutral forms, both of which are free in solution and adsorbed to the interface, and the ionization of verapamil at an interface changes with respect to its ionization in solution. From analyses of the pH dependency of surface binding and of solution and interfacial ionizations, we determined the values of the four equilibrium constants. These equilibrium constants permit correlative studies between the pH‐dependent abundance of each species and biologic activity. We discuss preliminary studies which indicate that the negative inotropic effect of verapamil is mediated by the membrane‐bound neutral form of the drug.
UR - http://www.scopus.com/inward/record.url?scp=0022971258&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0022971258&partnerID=8YFLogxK
U2 - 10.1002/jps.2600751014
DO - 10.1002/jps.2600751014
M3 - Article
C2 - 3795029
AN - SCOPUS:0022971258
SN - 0022-3549
VL - 75
SP - 976
EP - 982
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 10
ER -