Preclinical pharmacology of FG5893: a potential anxiolytic drug with high affinity for both 5-HT1A and 5-HT2A receptors

Albinsson, Agneta; Björk, Anders; Svartengren, Jan; Klint, Thorsten; Andersson, Gunnar

doi:10.1016/0014-2999(94)90119-8

Cited by 39 publications

(23 citation statements)

References 40 publications

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“…However, FG5893 is also a potent 5-HT2A receptor antagonist (48) and MDL 73005EF has lower affinity for 5-HT1A receptors than MKC-242 (51). Furthermore, it is noteworthy that MKC-242 contrasts with azapirones in the following respects: First, MKC-242 can not give rise to 1-(2-pyrimidyl) piperazine, a metabolite common to all the azapirones, which may reduce their therapeutic potential (11).…”

Section: Discussionmentioning

confidence: 99%

Novel Benzodioxan Derivative, 5-{3-[((2S)-1,4-Benzodioxan-2-ylmethyl)amino]propoxy}-l,3-benzodioxole HC1 (MKC-242), with a Highly Potent and Selective Agonist Activity at Rat Central Serotonin1A Receptors

Matsuda

Yoshikawa

Suzuki

et al. 1995

Japanese Journal of Pharmacology

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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,A (5-HTIA) receptors (K;: 0.35 nM) and moderate affinity for a,-adrenoceptors (K,: 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-HT,A-receptor-mediated responses (decreases in 5-HT turnover and 5-HT release) and postsynaptic 5-HT,A-receptor-mediated responses (hypothermia, an increase in serum corticosterone level and 5-HT,A behavioral syndrome). The effects of MKC-242 on decarboxylase inhibitor-induced 5-hydroxytryptophan accumulation and rectal temperature were blocked by the 5-HT,A-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,A-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-HT,A receptors, whereas the former had less efficacy than the latter at postsynaptic 5-HT,A 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,A receptors, respectively, in the central nervous system.

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Section: Discussionmentioning

confidence: 99%

Novel Benzodioxan Derivative, 5-{3-[((2S)-1,4-Benzodioxan-2-ylmethyl)amino]propoxy}-l,3-benzodioxole HC1 (MKC-242), with a Highly Potent and Selective Agonist Activity at Rat Central Serotonin1A Receptors

Matsuda

Yoshikawa

Suzuki

et al. 1995

Japanese Journal of Pharmacology

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“…These wide varieties of serotonin-induced motor function may depend on the subtypes of serotonergic receptors (5-HT 1 , 5-HT 2 , 5-HT 3 , 5-HT 4 , 5-HT 5 , 5-HT 6 , and 5-HT 7 ). Regarding the current study, m-chlorophenylpiperazine (mCPP), a nonselective 5-HT 2B/2C receptor agonist, is known to cause hypolocomotion in rats (Kennett and Curzon, 1988;Bonhaus et al, 1997;Kennett et al, 1997), and it has also been documented that 8-OH-DPAT, a 5-HT 1 receptor agonist, induces 5-HT 1 receptor-mediated 5-HT behavioral syndrome (Tricklebank et al, 1984;Albinsson et al, 1994;Hajos-Korcsok and Sharp, 1996). Recent studies have shown that the 5-HT 4 receptor is highly expressed not only in the peripheral organs, but also in many regions of the brain, such as the hippocampus, cerebral cortex, striatum, and limbic and basal ganglia structures (Domenech et al, 1994;Vilaro et al, 1996;Waeber et al, 1996;Compan et al, 1996), and the role of the 5-HT 4 receptor has been the subject of considerable investigation (Letty et al, 1997;Meneses and Hong, 1997a;Panocka et al, 1995;Semenova and Tiku, 1997).…”

Section: Introductionmentioning

confidence: 98%

5‐HT₄ receptors in the hippocampus modulate rat locomotor activity

et al. 2002

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In the present study, the ability of 5-hydroxytryptamine-4 (5-HT4) receptors in the hippocampus to enhance locomotor activity in rats was investigated by local infusion via microdialysis probes. The local infusion of 5-HT bilaterally into the striatum did not alter rat motor activity. The local infusion of 1.0 mM 5-HT into the bilateral hippocampus, but not lower doses, significantly increased motor activity as compared with the baseline values or the control rats. During the day hours (0700-1900, light on), the local infusion of either 5-HT4 agonist, 5-MeOT (100 microM) or mosapride (10 microM), but not in their lower concentrations, into the bilateral hippocampus significantly increased motor activity as compared with the baseline values or the control rats. Almost all increased motor activity was normal forward locomotion. This 5-MeOT-induced hyperlocomotion was completely reversed by the combined infusion of a 5-HT4 antagonist, either GR125487D (100 microM), SB204070 (100 microM) or RS23597-190 (100 microM). During the night hours (1900-0700, light off), the local infusion of either SB204070 (100 microM) or RS23597-190 (100 microM), but not in their lower concentrations, into the bilateral hippocampus significantly decreased rat motor activity and inhibited rat nocturnal hyperactivity. These hypoactivities during the night hours induced by 5-HT4 antagonist were reversed by the combined infusion of a 5-HT4 agonist, 5-MeOT (100 microM). The present study demonstrates that the serotonergic neurons projecting to the hippocampus, but not to the striatum, modulate rat locomotor activity by stimulating 5-HT4 receptors in the hippocampus.

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“…Antagonists or partial agonists of 5-HT 1A receptors have been postulated to be effective in the treatment of various psychiatric disorders [2] . Recently, it has been suggested that a combination of 5-HT 1A and 5-HT 2A receptor activity may facilitate the therapeutic action [3] , and this concept seems to gradually gain new support [4] .…”

Section: Introductionmentioning

confidence: 99%

“…We previously reported a series of N- [3-(4-aryl-1-piperazinyl)propyl] derivatives (1)(2)(3) in which modifications of the terminal amide fragment affected the 5-HT1A/5-HT2A receptor selectivity and/or enhanced the functional activity [5,6] . In the present study we prepared chain-extended analogues of those compounds to investigate the effect of an increasing distance between amide and 1-arylpiperazine functionalities on their in vitro and in vivo activity.…”

Section: Introductionmentioning

confidence: 99%

Novel 1,4-Benzoxazin-3(4H)-one, 1,2-Benzoxazolin-3-one and 1,3-Benzoxazolin-2,4-dione Arylpiperazine Derivatives with Different 5-HT1A and Antagonistic 5-HT2A Activities

Mokrosz¹,

Kowalski

Kowalska

et al. 1999

Arch. Pharm. Pharm. Med. Chem.

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Preclinical pharmacology of FG5893: a potential anxiolytic drug with high affinity for both 5-HT1A and 5-HT2A receptors

Cited by 39 publications

References 40 publications

Novel Benzodioxan Derivative, 5-{3-[((2S)-1,4-Benzodioxan-2-ylmethyl)amino]propoxy}-l,3-benzodioxole HC1 (MKC-242), with a Highly Potent and Selective Agonist Activity at Rat Central Serotonin1A Receptors

Novel Benzodioxan Derivative, 5-{3-[((2S)-1,4-Benzodioxan-2-ylmethyl)amino]propoxy}-l,3-benzodioxole HC1 (MKC-242), with a Highly Potent and Selective Agonist Activity at Rat Central Serotonin1A Receptors

5‐HT₄ receptors in the hippocampus modulate rat locomotor activity

Novel 1,4-Benzoxazin-3(4H)-one, 1,2-Benzoxazolin-3-one and 1,3-Benzoxazolin-2,4-dione Arylpiperazine Derivatives with Different 5-HT1A and Antagonistic 5-HT2A Activities

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Preclinical pharmacology of FG5893: a potential anxiolytic drug with high affinity for both 5-HT1A and 5-HT2A receptors

Cited by 39 publications

References 40 publications

Novel Benzodioxan Derivative, 5-{3-[((2S)-1,4-Benzodioxan-2-ylmethyl)amino]propoxy}-l,3-benzodioxole HC1 (MKC-242), with a Highly Potent and Selective Agonist Activity at Rat Central Serotonin1A Receptors

Novel Benzodioxan Derivative, 5-{3-[((2S)-1,4-Benzodioxan-2-ylmethyl)amino]propoxy}-l,3-benzodioxole HC1 (MKC-242), with a Highly Potent and Selective Agonist Activity at Rat Central Serotonin1A Receptors

5‐HT4 receptors in the hippocampus modulate rat locomotor activity

Novel 1,4-Benzoxazin-3(4H)-one, 1,2-Benzoxazolin-3-one and 1,3-Benzoxazolin-2,4-dione Arylpiperazine Derivatives with Different 5-HT1A and Antagonistic 5-HT2A Activities

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5‐HT₄ receptors in the hippocampus modulate rat locomotor activity