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

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.