Jpn. J. Pharmacol. 69, 357-366 (1995)

Novel Benzodioxan Derivative, 5-{3-[((2S)- 1,4-Benzodioxan- 2-ylmethyl)-amino]propoxy}- 1,3-benzodioxole HCI (MKC-242), with a Highly Potent and Selective Agonist Activity at Rat Central Serotonin1A Receptors

Toshio Matsuda (1), Takashi Yoshikawa (1), Makoto Suzuki (1), Shoichi Asano (1), Pranee Somboonthum (1), Kazuhiro Takuma (1), Yoshihide Nakano (1), Tomoko Morita (1), Yukiko Nakasu (1), Hye Sun Kim (1), Mitsuo Egawa (2), Akihiro Tobe (2) and Akemichi Baba (1,*)

(1) Department of Pharmacology, Faculty of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565, Japan
(2) Research and Development Department, Mitsubishi Chemical Co., Shinagawa-ku, Tokyo 140, Japan
(*) To whom correspondence should be addressed.

Abstract: The present study characterizes the neurochemical profile of the newly synthesized compound 5-{3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy}-1,3-benzodioxole HCI (MKC-242). In in vitro experiments, MKC-242 had high affinity for serotonin1A (5-HT1A) receptors (Ki: 0.35 nM) and moderate affinity for alpha1-adrenoceptors (Ki: 21 nM), whereas it had no appreciable affinity for any other neurotransmitter recognition sites studied and 5-HT transporter. MKC-242 (0.3-3.0 mg/kg, s.c.; 1-10 mg/kg, p.o.) caused presynaptic 5-HT1A-receptor-mediated responses (decreases in 5-HT turnover and 5-HT release) and postsynaptic 5-HT1A-receptor-mediated responses (hypothermia, an increase in serum corticosterone level and 5-HT1A behavioral syndrome). The effects of MKC-242 on decarboxylase inhibitor-induced 5-hydroxytryptophan accumulation and rectal temperature were blocked by the 5-HT1A-receptor antagonist N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropanamide. The comparative studies on the in vivo responses induced by MKC-242 and the 5-HT1A-receptor full agonist 8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) showed that MKC-242 and 8-OH-DPAT had similar efficacy at presynaptic 5- HT1A receptors, whereas the former had less efficacy than the latter at postsynaptic 5-HT1A receptors. Furthermore, MKC-242 partially inhibited forskolin-stimulated adenylate cyclase activity in hippocampal membranes. These findings suggest that MKC-242 acts as a full and partial agonist at pre- and postsynaptic 5-HTIA receptors, respectively, in the central nervous system.

Keywords: Serotonin (5-HT), 5-HT1A receptor, MKC-242, Agonist

Copyright© The Japanese Pharmacological Society 1995

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