Shoichi Asano (1), Toshio Matsuda (1), Takashi Yoshikawa (1), Pranee Somboonthum (1), Hatsue Tasaki (1), Michikazu Abe (2) and Akemichi Baba (1,*)
(1) Department of Pharmacology, Faculty of Pharmaceutical Sciences, Osaka
University, 1-6 Yamada-oka, Suita, Osaka 565, Japan
(2) Pharmaceuticals Laboratory I, Yokohama Research Center, Mitsubishi Chemical
Corporation, Yokohama 227, Japan
(*) To whom correspondence should be addressed.
Abstract: The present study was carried out to clarify whether orally administered 5-{3-[((2S)-1,4 benzodioxan-2-ylmethyl)amino]propoxy}-1,3-benzodioxole (MKC-242), a serotonin1A (5-HT1A)-receptor agonist having potent anxiolytic-like and antidepressant-like effects in animal models, binds to 5-HT1A receptors in rat brain. Quantitative autoradiography showed that orally administered MKC-242 (0.1 - 0.5 mg/kg) caused a significant decrease in [3H]8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) binding in the hippocampus and dorsal raphe nucleus sections. The decrease in the binding by MKC-242 was observed up to 4 hr after administration, and the effective doses were similar to those in its anxiolytic-like effect in the animal models. Repeated treatment of MKC-242 (0.5 mg/kg/day, p.o.) or buspirone (30 mg/kg/day, p.o.) for 2 weeks did not affect [3H]8-OH-DPAT binding in both sections. These results suggest that orally administered MKC-242 at the low doses that do not show 5-HT1A-receptor-mediated in vivo responses such as the hypothermic effect, adrenocortical effect and the decrease in 5-HT turnover passes the blood-brain barrier and subsequently binds to 5-HT1A receptors in rat brain. In addition, they indicate that repeated stimulation of the receptors by the agonists does not affect the number of the binding sites.
Keywords: 5-{3-[((2S)-1,4-Benzodioxan-2-ylmethyl)amino]propoxy}-1,3-benzodioxole (MKC-242), 5-HT1A-receptor agonist, Autoradiography, Anxiolytic