NOVEL BENZODIOXAN DERIVATIVE, ODIOXAN-2-YLMETHYL)AMINO]PROPOXY)-1,3-BENZODIOXOLE HCL (MKC-242), WITH A HIGHLY POTENT AND SELECTIVE AGONIST ACTIVITY AT RAT CENTRAL SEROTONIN(1A) RECEPTORS
T. Matsuda et al., NOVEL BENZODIOXAN DERIVATIVE, ODIOXAN-2-YLMETHYL)AMINO]PROPOXY)-1,3-BENZODIOXOLE HCL (MKC-242), WITH A HIGHLY POTENT AND SELECTIVE AGONIST ACTIVITY AT RAT CENTRAL SEROTONIN(1A) RECEPTORS, Japanese Journal of Pharmacology, 69(4), 1995, pp. 357-366
The present study characterizes the neurochemical profile of the newly
synthesized compound 3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propox
y} HCl (MKC-242). In in vitro experiments, MKC-242 had high affinity f
or serotonin(1A) (5-HT1A) receptors (K-i: 0.35 nM) and moderate affini
ty for alpha(1)-adrenoceptors (K-i: 21 nM), whereas it had no apprecia
ble 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-media
ted responses (hypothermia, an increase in serum corticosterone level
and 5-HT1A behavioral syndrome). The effects of MKC-242 on decarboxyla
se inhibitor-induced 5-hydroxytryptophan accumulation and rectal tempe
rature were blocked by the 5-HT1A-receptor antagonist methoxyphenyl)pi
perazin-1-yl)-2-phenylpropanamide. The comparative studies on the in v
ivo responses induced by MKC-242 and the 5-HT1A-receptor full agonist
8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) showed that MKC-242
and 8-OH-DPAT had similar efficacy at presynaptic 5-HT1A receptors, w
hereas the former had less efficacy than th(: latter at postsynaptic 5
-HT1A receptors. Furthermore, MKC-242 partially inhibited forskolin-st
imulated adenylate cyclase activity in hippocampal membranes. These fi
ndings suggest that MKC-242 acts as a full and partial agonist at pre-
and postsynaptic 5-HT1A receptors, respectively, in the central nervo
us system.