Novel Benzodioxan Derivative, 5-{ 3- [((2S)-1, 4-Benzodioxan-2-ylmethyl)amino] propoxy} -1, 3-benzodioxole HC1 (MKC-242), with a Highly Potent and Selective Agonist Activity at Rat Central SerotoninlA Receptors

Toshio Matsuda; Takashi Yoshikawa; Makoto Suzuki; Shoichi Asano; Pranee Somboonthum; Kazuhiro Takuma; Yoshihide Nakano; Tomoko Morita; Yukiko Nakasu; Hye Sun Kim; Mitsuo Egawa; Akihiro Tobe; Akemichi Baba

doi:10.1254/jjp.69.357

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

Author information

Toshio Matsuda
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Osaka University
Takashi Yoshikawa
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Osaka University
Makoto Suzuki
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Osaka University
Shoichi Asano
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Osaka University
Pranee Somboonthum
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Osaka University
Kazuhiro Takuma
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Osaka University
Yoshihide Nakano
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Osaka University
Tomoko Morita
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Osaka University
Yukiko Nakasu
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Osaka University
Hye Sun Kim
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Osaka University
Mitsuo Egawa
Research and Development Department, Mitsubishi Chemical Co.
Akihiro Tobe
Research and Development Department, Mitsubishi Chemical Co.
Akemichi Baba
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Osaka University

Keywords: Serotonin (5-HT), 5-HT_1A receptor, MKC-242, Agonist

JOURNAL FREE ACCESS

1995 Volume 69 Issue 4 Pages 357-366

DOI https://doi.org/10.1254/jjp.69.357

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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 HC1 (MKC-242). In in vitro experiments, MKC-242 had high affinity for serotonin_1A (5-HT_1A) receptors (K₁: 0.35 nM) and moderate affinity for α₁-adrenoceptors (K_i: 21 nM), whereas it had no appreciable affinity for any other neurotrans-mitter 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-HT_1A-receptor-mediated responses (decreases in 5-HT turnover and 5-HT release) and postsynaptic 5-HT_1A-receptor-mediated responses (hypothermia, an increase in serum corticosterone level and 5-HT_1A behavioral syndrome). The effects of MKC-242 on decarboxylase inhibitor-induced 5-hydroxytryptophan accumulation and rectal temperature were blocked by the 5-HT_1A-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-HT_1A-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-HT_1A receptors, whereas the former had less efficacy than the latter at postsynaptic 5-HT_1A 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-HT_1A receptors, respectively, in the central nervous system.

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