A competitive interaction model predicts the effect of WAY-100,635 on the time course of R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin-induced hypothermia.
The objective of this investigation was to characterize quantitatively the pharmacodynamic interaction between N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamide (WAY-100,635) and R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT) in vivo. The 8-OH-DPAT-induced change in body temperature was used as a pharmacodynamic endpoint. Four groups of rats each received 1 mg/kg 8-OH-DPAT in 5 min during computer-controlled infusions of physiological saline or WAY-100,635, targeted at steady-state concentrations of 20, 85, and 170 ng/ml. Body temperature was monitored continuously with a telemetric system, and frequent blood samples were obtained to determine the pharmacokinetics of both drugs. Large differences in pharmacokinetics were observed between WAY-100,635 and R-8-OH-DPAT, reflected in values of the terminal elimination half-life of 33 and 143 min, respectively. Infusion of WAY-100,635 had no influence on the pharmacokinetics of R-8-OH-DPAT. With regard to the pharmacodynamics, clear antagonism of the R-8-OH-DPAT-induced hypothermia was observed. The complex pharmacological effect versus time profiles of R-8-OH-DPAT were analyzed on the basis of an indirect physiological response model with set point control coupled to a competitive interaction model for an agonist and antagonist acting at a common receptor. This model converged, yielding precise estimates of the pharmacodynamic parameters of both WAY-100,635 and R-8-OH-DPAT, which were independent of the infusion rate of WAY-100,635. The estimated in vivo binding constant of WAY-100,635 was 0.98 ng/ml (2.3 nM), which is very similar to the reported value from in vitro receptor binding assays. The findings of this investigation show that, in contrast to earlier reports in the literature, WAY 100,635 behaves as a pure competitive antagonist at the 5-hydroxytryptamine(1A) receptor in vivo.
Zuideveld
Klaas P
KP
Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Sylvius Laboratory, Leiden, The Netherlands.
Treijtel
Nicoline
N
Maas
Hugo J
HJ
Gubbens-Stibbe
Josy M
JM
Peletier
Lambertus A
LA
van Der Graaf
Piet H
PH
Danhof
Meindert
M
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000465:Algorithms; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007035:Hypothermia / Q000139:chemically induced*; D007262:Infusions, Intravenous; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D010879:Piperazines / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D011725:Pyridines / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin