RT Journal Article
SR Electronic
T1 Binding of benzodiazepines and some major metabolites at their sites in normal human frontal cortex in vitro.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 897
OP 901
VO 256
IS 3
A1 E Richelson
A1 A Nelson
A1 R Neeper
YR 1991
UL http://jpet.aspetjournals.org/content/256/3/897.abstract
AB Using [3H]flunitrazepam in radioligand binding assays, we determined equilibrium dissociation constants (Kd's) at 37 degrees C for 22 benzodiazepines (15 parent compounds and 7 major metabolites) at benzodiazepine binding sites in human frontal cortex. This list included several compounds never studied before at human receptors. Although dissociation was too rapid to measure reliably at this temperature, the Kd's for flunitrazepam were not significantly different when either rapid filtration or centrifugation was used to separate the bound from free radioligand. The most potent compound was triazolam (Kd = 0.54 nM); the least potent, chlordiazepoxide (Kd = 684 nM). The Kd's were significantly lower (about 3- to 7-fold) for several compounds tested at an equilibrium temperature of 0 degrees C compared to those obtained at 37 degrees C. There was a strong correlation for 15 compounds for the log Kd at rat brain receptors (data obtained from the literature) vs. the log Kd for human brain. In addition, the log Kd's of the various benzodiazepines for their receptor were significantly correlated with the log of their minimum daily dosages used to treat patients. Many of the benzodiazepines have clinically important active metabolites that have higher affinity for benzodiazepine binding sites in human brain than their parent compounds. Such data have important implications in the clinical use of these compounds.