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Herbert Y. Meltzer - One of the best experts on this subject based on the ideXlab platform.

  • neurosteroid pregnenolone sulfate alone and as augmentation of lurasidone or Tandospirone rescues phencyclidine induced deficits in cognitive function and social interaction
    Behavioural Brain Research, 2018
    Co-Authors: Lakshmi Rajagopal, D Soni, Herbert Y. Meltzer
    Abstract:

    Abstract Background Pregnenolone sulfate (PregS), an endogenous neurosteroid, which negatively and positively modulates gamma amino butyric acid subunit A (GABA A ) and N-methyl D-aspartate (NMDA) receptors (R) respectively, among other potential neuroplastic changes on synaptic processes, has shown some beneficial effects on treating cognitive impairment associated with schizophrenia (CIAS) and negative symptoms. Lurasidone (Lur), an atypical antipsychotic drug (AAPD), and Tandospirone (Tan), a 5-HT 1A  R partial agonist, have also been reported to improve cognitive or negative symptoms, or both, in some schizophrenia patients. Methods We tested whether PregS, by itself, and in combination with Lur or Tan could rescue persistent deficits produced by subchronic treatment with the NMDAR antagonist, phencyclidine (PCP)-in episodic memory, executive functioning, and social behavior, using novel object recognition (NOR), operant reversal learning (ORL), and social interaction (SI) tasks, in male C57BL/6 J mice. Results PregS (10, but not 3 mg/kg) significantly rescued subchronic PCP-induced NOR and SI deficits. Co-administration of sub-effective doses (SEDs) of PregS (3 mg/kg) + Lur (0.1 mg/kg) or Tan (0.03 mg/kg) rescued scPCP-induced NOR and SI deficits. Further, PregS (30, but not 10 mg/kg) rescued PCP-induced ORL deficit, as did the combination of SED PregS (10 mg/kg) +SED Lur (1 mg/kg) or Tan (1 mg/kg). Conclusion PregS was effective alone and as adjunctive treatment for treating two types of cognitive impairments and negative symptoms in this schizophrenia model. Further study of the mechanisms by which PregS alone and in combination with AAPDs and 5-HT 1A  R partial agonists, rescues the deficits in cognition and SI in this preclinical model is indicated.

  • blonanserin reverses the phencyclidine pcp induced impairment in novel object recognition nor in rats role of indirect 5 ht1a partial agonism
    Behavioural Brain Research, 2013
    Co-Authors: Masakuni Horiguchi, Herbert Y. Meltzer
    Abstract:

    Blonanserin is an atypical antipsychotic drug (APD) which, compared to other atypical APDs, is a relatively selective serotonin (5-HT)2A and dopamine D2 antagonist. Comparing blonanserin with more broadly acting atypical APDs could be useful to test the contributions of actions at other monoamine receptors, e.g. 5-HT1A receptors, to the reversal of PCP-induced novel object recognition (NOR) deficit. In this study, we tested the effect of blonanserin alone, and in combination with 5-HT1A agents, on NOR deficit induced by subchronic treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP; 2 mg/kg), b.i.d., for 7 days. Blonanserin, 1mg/kg, but not 0.3mg/kg, improved the PCP-induced NOR deficit. However, at 1mg/kg, object exploration was diminished. Co-administration of sub-effective doses of blonanserin (0.3 mg/kg) and the 5-HT1A partial agonist, Tandospirone (0.2 mg/kg), significantly reversed the NOR deficit without diminishing activity during the acquisition or retention periods. The combination of WAY100635 (0.6 mg/kg), a 5-HT1A antagonist, and blonanserin (1 mg/kg), also diminished object exploration which prevented assessment of the effect of this combination on NOR. WAY100635 (0.6 mg/kg) blocked the ameliorating effect of risperidone (0.1 mg/kg), another atypical APD with low affinity for 5-HT1A receptors, but did not impair exploration. These results suggest that blonansein and risperidone, atypical APDs which lack a direct action on 5-HT1A receptors require 5-HT1A receptor stimulation to reverse the subchronic PCP-induced NOR deficit and provide a support for clinical trial of blonanserin in combination with Tandospirone to ameliorate cognitive impairment in schizophrenia and to have fewer side effects.

  • D1 receptor agonists reverse the subchronic phencyclidine (PCP)-induced novel object recognition (NOR) deficit in female rats
    Behavioural brain research, 2012
    Co-Authors: Masakuni Horiguchi, Kayleen E Hannaway, Adesewa E Adelekun, Karu Jayathilake, Mei Huang, Herbert Y. Meltzer
    Abstract:

    Development of dopamine (DA) D(1) receptor agonists is a priority to improve cognitive impairment in schizophrenia (CIS). This study examined the dose-response relationship of the selective D(1) agonist, SKF38393 (0.5-40 mg/kg), to reverse the deficit in novel object recognition (NOR), an analog of declarative memory in man, produced by subchronic phencyclidine (PCP), an N-methyl-D-aspartate (NMDA) receptor non-competitive antagonist, and the ability of the D(1) antagonists, SCH23390 (0.05 mg/kg) and SKF83566 (0.15 mg/kg), to impair NOR in normal Long-Evans female rats. We also examined the ability of Tandospirone, a serotonin (5-HT)(1A) receptor partial agonist, and LY341495, a mGluR2/3 receptor antagonist, to potentiate or block the effects of SKF38393 on NOR, respectively. SKF38393 reversed the persistent NOR deficit produced by subchronic PCP; the dose-response curve for SKF38393 was an inverted U-shape, with the peak effect at 6 mg/kg. SKF83566 and SCH23390 impaired NOR in normal rats. Co-administration of sub-effective doses of SKF38393 (0.25 mg/kg) and Tandospirone (0.2 mg/kg) improved the PCP-induced NOR deficit, while LY341495 (1 mg/kg) blocked the ameliorating effect of SKF38393 (6 mg/kg), respectively. These data provide the first evidence that the reversal of the PCP-induced NOR deficit by D(1) agonism has an inverted U-shaped dose-response curve and that 5-HT(1A) and mGluR2/3 receptor signalling facilitates the efficacy of D(1) agonism to improve these deficits. These data suggest that although D(1) agonists may be useful to improve CIS, these agents, particularly higher doses, may also worsen cognitive function in some patients, because of an inverted U-shaped dose response curve.

  • the role of 5 ht1a receptors in phencyclidine pcp induced novel object recognition nor deficit in rats
    Psychopharmacology, 2012
    Co-Authors: Masakuni Horiguchi, Herbert Y. Meltzer
    Abstract:

    Rationale Atypical antipsychotic drugs (APDs), many of which are direct or indirect serotonin (5-HT)1A agonists, and Tandospirone, a 5-HT1A partial agonist, have been reported to improve cognition in schizophrenia.

  • effect of buspirone a serotonin1a partial agonist on cognitive function in schizophrenia a randomized double blind placebo controlled study
    Schizophrenia Research, 2007
    Co-Authors: Karu Jayathilake, Tomiki Sumiyoshi, Sohee Park, Ajanta Roy, Aygun Ertugrul, Herbert Y. Meltzer
    Abstract:

    Inpreviousstudies,wedemonstratedthatTandospirone,aserotonin-5-HT1Apartialagonist,addedtoongoingtreatmentwithsmall to moderate doses of typical antipsychotic drugs, improved executive function and verbal learning and memory. However, Tandospirone is not available in most countries, and atypical antipsychotic drugs (AAPDs) have largely replaced typical antipsychotic drugsastheprimarytreatmentforschizophrenia.Therefore,thegoalofthisrandomlyassignedplacebo-controlled double-blindstudy wastodetermineiftheadditionofbuspirone,awidelyavailable5-HT1Apartialagonist,wouldenhancecognitivefunction,insubjects with schizophrenia treated with AAPDs. Seventy-three patients with schizophrenia, who had been treated with an AAPD for at least three months, were randomly assigned to receive either buspirone, 30 mg/day, or matching placebo. All other medications remained unchanged. Attention, verbal fluency, verbal learning and memory, verbal working memory, and executive function, as well as psychopathology, were assessed at baseline, and 6 weeks, and 3 and 6 months after baseline. A significant Time×Group interaction effect was noted on the Digit Symbol Substitution Test, a measure of attention/speeded motor performance, due to better performance of the buspirone group compared to the placebo group at 3 months. No significant interaction effects were noted for other domains of cognition. Scores on the Brief Psychiatric Rating Scale (Total, Positive) were improved during treatment with buspirone but not placebo, but the effects did not reach statistical significance. The results of this study showed a possible benefit of buspirone augmentation of AAPDs to enhance attention. However, we did not replicate the results of the previous study with Tandospirone, which may be due to the differences between Tandospirone and buspirone, between typical antipsychotics and AAPDs, or a combination of the above. Further study to determine the usefulness of 5-HT1A agonist treatment in schizophrenia is indicated. © 2007 Elsevier B.V. All rights reserved.

M Egawa - One of the best experts on this subject based on the ideXlab platform.

  • novel benzodioxan derivative 5 3 2s 1 4 benzodioxan 2 ylmethyl amino propoxy 1 3 benzodioxole hcl mkc 242 with anxiolytic like and antidepressant like effects in animal models
    Journal of Pharmacology and Experimental Therapeutics, 1996
    Co-Authors: M Abe, Kenichi Saito, R Tabata, Toshio Matsuda, A Baba, M Egawa
    Abstract:

    Behavioral effects of MKC-242 (5-{3-[((2>)-1,4-benzodioxan-2-ylmethyl)amino] propoxy}-1,3-benzodioxole CHl), a novel and selective serotonin 1A receptor agonist, were investigated in rats and mice and compared against those of diazepam, buspirone and Tandospirone. MKC-242 (0.0625-0.25 mg/kg, p.o.) significantly increased punished drinking in water-deprived rats. The reference compounds also increased punished drinking at doses of 10 to 40 mg/kg, p.o. The increase by MKC-242 was blocked by N-tert-butyl-3-(4-(2-methoxypenyl)piperazin-1-yl) -2-phenylpropanamide, a serotonin 1A receptor antagonist. MKC-242 (0.1-0.5 mg/kg, p.o.) also increased social interaction under high light and unfamiliar conditions in rats. It had weak benzodiazepine-like side effects in mice. MKC-242 (1, 3 mg/kg, p.o.) attenuated the reduction of locomotion caused by restraint stress in rats, the same effects were observed on both buspirone (100 mg/kg, p.o.) and Tandospirone (100 mg/kg, p.o.). In the forced swimming test in rats, MKC-242 (0.3-3 mg/kg, i.p.), 8-hydroxy-2-(di-n-propylamino) tetralin (1, 3 mg/kg, i.p.) and amitriptyline (30 mg/kg, i.p.) reduced immobility, although diazepam, buspirone and Tandospirone did not. The reduction by MKC-242 and 8-OH-DPAT was antagonized by N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl) -2-phenylpropanamide. Moreover, the reduction was also blocked by 1-(2--pyrimidinyl)piperazine (1-PP), a common metabolite of buspirone and Tandospirone. These findings suggest that MKC-242 possesses potent anxiolytic and antidepressant properties that are mediated via an activation of serotonin 1A receptors.

Masakuni Horiguchi - One of the best experts on this subject based on the ideXlab platform.

  • prolonged reversal of the phencyclidine induced impairment in novel object recognition by a serotonin 5 ht 1a dependent mechanism
    Behavioural Brain Research, 2016
    Co-Authors: Masakuni Horiguchi, Masanori Miyauchi, Nichole M Neugebauer, Yoshihiro Oyamada
    Abstract:

    Abstract Many acute treatments transiently reverse the deficit in novel object recognition (NOR) produced by subchronic treatment with the N -methyl- d -aspartate receptor non-competitive antagonist, phencyclidine (PCP), in rodents. Treatments which restore NOR for prolonged periods after subchronic PCP treatment may have greater relevance for treating the cognitive impairment in schizophrenia than those which restore NOR transiently. We examined the ability of post-PCP subchronic lurasidone, an atypical APD with potent serotonin (5-HT) 1A partial agonism and subchronic Tandospirone, a selective 5-HT 1A partial agonist, to enable prolonged reversal of the subchronic PCP-induced NOR deficit. Rats treated with subchronic PCP (2 mg/kg, twice daily for 7 days) or vehicle, followed by a 7 day washout period were subsequently administered lurasidone or Tandospirone twice daily for 7 days (day 15–21), and tested for NOR weekly for up to two additional weeks. Subchronic lurasidone (1, but not 0.1 mg/kg) or Tandospirone (5, but not 0.6 mg/kg) significantly reversed the PCP-induced NOR deficit at 24 h and 7days after the last injection, respectively. The effect of lurasidone persisted for one more week (day 36, 14 days after the last lurasidone dose), while Tandospirone-treated rats were able to perform NOR at 7, but not 14, days after the last Tandospirone dose. Co-administration of WAY100635 (0.6 mg/kg), a 5-HT 1A antagonist, with lurasidone, blocked the ability of lurasidone to restore NOR, suggesting that 5-HT 1A receptor stimulation is necessary for lurasidone to reverse the effects of PCP. The role of dopamine, GABA and the MAPK/ERK signalling pathway in the persistent, but not indefinite, restoration of NOR is discussed.

  • combined serotonin 5 ht 1a agonism 5 ht2a and dopamine d2 receptor antagonism reproduces atypical antipsychotic drug effects on phencyclidine impaired novel object recognition in rats
    Behavioural Brain Research, 2015
    Co-Authors: Yoshihiro Oyamada, Masakuni Horiguchi, Lakshmi Rajagopal, Masanori Miyauchi, H. Y. Meltzer
    Abstract:

    Abstract Subchronic administration of an N-methyl- d -aspartate receptor (NMDAR) antagonist, e.g. phencyclidine (PCP), produces prolonged impairment of novel object recognition (NOR), suggesting they constitute a hypoglutamate-based model of cognitive impairment in schizophrenia (CIS). Acute administration of atypical, e.g. lurasidone, but not typical antipsychotic drugs (APDs), e.g. haloperidol, are able to restore NOR following PCP (acute reversal model). Furthermore, atypical APDs, when co-administered with PCP, have been shown to prevent development of NOR deficits (prevention model). Most atypical, but not typical APDs, are more potent 5-HT 2A receptor inverse agonists than dopamine (DA) D 2 antagonists, and have been shown to enhance cortical and hippocampal efflux and to be direct or indirect 5-HT 1A agonists in vivo. To further clarify the importance of these actions to the restoration of NOR by atypical APDs, sub-effective or non-effective doses of combinations of the 5-HT 1A partial agonist (Tandospirone), the 5-HT 2A inverse agonist (pimavanserin), or the D 2 antagonist (haloperidol), as well as the combination of all three agents, were studied in the acute reversal and prevention PCP models of CIS. Only the combination of all three agents restored NOR and prevented the development of PCP-induced deficit. Thus, this triple combination of 5-HT 1A agonism, 5-HT 2A antagonism/inverse agonism, and D 2 antagonism is able to mimic the ability of atypical APDs to prevent or ameliorate the PCP-induced NOR deficit, possibly by stimulating signaling cascades from D 1 and 5-HT 1A receptor stimulation, modulated by D 2 and 5-HT 2A receptor antagonism.

  • blonanserin reverses the phencyclidine pcp induced impairment in novel object recognition nor in rats role of indirect 5 ht1a partial agonism
    Behavioural Brain Research, 2013
    Co-Authors: Masakuni Horiguchi, Herbert Y. Meltzer
    Abstract:

    Blonanserin is an atypical antipsychotic drug (APD) which, compared to other atypical APDs, is a relatively selective serotonin (5-HT)2A and dopamine D2 antagonist. Comparing blonanserin with more broadly acting atypical APDs could be useful to test the contributions of actions at other monoamine receptors, e.g. 5-HT1A receptors, to the reversal of PCP-induced novel object recognition (NOR) deficit. In this study, we tested the effect of blonanserin alone, and in combination with 5-HT1A agents, on NOR deficit induced by subchronic treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP; 2 mg/kg), b.i.d., for 7 days. Blonanserin, 1mg/kg, but not 0.3mg/kg, improved the PCP-induced NOR deficit. However, at 1mg/kg, object exploration was diminished. Co-administration of sub-effective doses of blonanserin (0.3 mg/kg) and the 5-HT1A partial agonist, Tandospirone (0.2 mg/kg), significantly reversed the NOR deficit without diminishing activity during the acquisition or retention periods. The combination of WAY100635 (0.6 mg/kg), a 5-HT1A antagonist, and blonanserin (1 mg/kg), also diminished object exploration which prevented assessment of the effect of this combination on NOR. WAY100635 (0.6 mg/kg) blocked the ameliorating effect of risperidone (0.1 mg/kg), another atypical APD with low affinity for 5-HT1A receptors, but did not impair exploration. These results suggest that blonansein and risperidone, atypical APDs which lack a direct action on 5-HT1A receptors require 5-HT1A receptor stimulation to reverse the subchronic PCP-induced NOR deficit and provide a support for clinical trial of blonanserin in combination with Tandospirone to ameliorate cognitive impairment in schizophrenia and to have fewer side effects.

  • D1 receptor agonists reverse the subchronic phencyclidine (PCP)-induced novel object recognition (NOR) deficit in female rats
    Behavioural brain research, 2012
    Co-Authors: Masakuni Horiguchi, Kayleen E Hannaway, Adesewa E Adelekun, Karu Jayathilake, Mei Huang, Herbert Y. Meltzer
    Abstract:

    Development of dopamine (DA) D(1) receptor agonists is a priority to improve cognitive impairment in schizophrenia (CIS). This study examined the dose-response relationship of the selective D(1) agonist, SKF38393 (0.5-40 mg/kg), to reverse the deficit in novel object recognition (NOR), an analog of declarative memory in man, produced by subchronic phencyclidine (PCP), an N-methyl-D-aspartate (NMDA) receptor non-competitive antagonist, and the ability of the D(1) antagonists, SCH23390 (0.05 mg/kg) and SKF83566 (0.15 mg/kg), to impair NOR in normal Long-Evans female rats. We also examined the ability of Tandospirone, a serotonin (5-HT)(1A) receptor partial agonist, and LY341495, a mGluR2/3 receptor antagonist, to potentiate or block the effects of SKF38393 on NOR, respectively. SKF38393 reversed the persistent NOR deficit produced by subchronic PCP; the dose-response curve for SKF38393 was an inverted U-shape, with the peak effect at 6 mg/kg. SKF83566 and SCH23390 impaired NOR in normal rats. Co-administration of sub-effective doses of SKF38393 (0.25 mg/kg) and Tandospirone (0.2 mg/kg) improved the PCP-induced NOR deficit, while LY341495 (1 mg/kg) blocked the ameliorating effect of SKF38393 (6 mg/kg), respectively. These data provide the first evidence that the reversal of the PCP-induced NOR deficit by D(1) agonism has an inverted U-shaped dose-response curve and that 5-HT(1A) and mGluR2/3 receptor signalling facilitates the efficacy of D(1) agonism to improve these deficits. These data suggest that although D(1) agonists may be useful to improve CIS, these agents, particularly higher doses, may also worsen cognitive function in some patients, because of an inverted U-shaped dose response curve.

  • Prevention of the Phencyclidine-Induced Impairment in Novel Object Recognition in Female Rats by Co-Administration of Lurasidone or Tandospirone, a 5-HT_1A Partial Agonist
    Neuropsychopharmacology, 2012
    Co-Authors: Masakuni Horiguchi, Kayleen E Hannaway, Adesewa E Adelekun, Karu Jayathilake
    Abstract:

    Hypoglutamatergic function may contribute to cognitive impairment in schizophrenia (CIS). Subchronic treatment with the N -methyl- D -aspartate receptor antagonist, phencyclidine (PCP), induces enduring deficits in novel object recognition (NOR) in rodents. Acute treatment with atypical antipsychotic drugs (APDs), which are serotonin (5-HT)_2A/dopamine D_2 antagonists, but not typical APDs, eg, haloperidol, reverses the PCP-induced NOR deficit in rats. We have tested the ability of lurasidone, an atypical APD with potent 5-HT_1A partial agonist properties, Tandospirone, a selective 5-HT_1A partial agonist, haloperidol, a D_2 antagonist, and pimavanserin, a 5-HT_2A inverse agonist, to prevent the development of the PCP-induced NOR deficit. Rats were administered lurasidone (0.1 or 1 mg/kg), Tandospirone (5 mg/kg), pimavanserin (3 mg/kg), or haloperidol (1 mg/kg) b.i.d. 30 min before PCP (2 mg/kg, b.i.d.) for 7 days (day1–7), followed by a 7-day washout (day8–14). Subchronic treatment with PCP induced an enduring NOR deficit. Lurasidone (1 mg/kg) but not 0.1 mg/kg, which is effective to acutely reverse the deficit due to subchronic PCP, or Tandospirone, but not pimavanserin or haloperidol, significantly prevented the PCP-induced NOR deficit on day 15. The ability of lurasidone co-treatment to prevent the PCP-induced NOR deficit was enduring and still present at day 22. The preventive effect of lurasidone was blocked by WAY100635, a selective 5-HT_1A antagonists, further evidence for the importance of 5-HT_1A receptor stimulation in the NOR deficit produced by subchronic PCP. Further study is needed to determine whether these results concerning mechanism and dosage can be the basis for prevention of the development of CIS in at risk populations.

M Abe - One of the best experts on this subject based on the ideXlab platform.

  • novel benzodioxan derivative 5 3 2s 1 4 benzodioxan 2 ylmethyl amino propoxy 1 3 benzodioxole hcl mkc 242 with anxiolytic like and antidepressant like effects in animal models
    Journal of Pharmacology and Experimental Therapeutics, 1996
    Co-Authors: M Abe, Kenichi Saito, R Tabata, Toshio Matsuda, A Baba, M Egawa
    Abstract:

    Behavioral effects of MKC-242 (5-{3-[((2>)-1,4-benzodioxan-2-ylmethyl)amino] propoxy}-1,3-benzodioxole CHl), a novel and selective serotonin 1A receptor agonist, were investigated in rats and mice and compared against those of diazepam, buspirone and Tandospirone. MKC-242 (0.0625-0.25 mg/kg, p.o.) significantly increased punished drinking in water-deprived rats. The reference compounds also increased punished drinking at doses of 10 to 40 mg/kg, p.o. The increase by MKC-242 was blocked by N-tert-butyl-3-(4-(2-methoxypenyl)piperazin-1-yl) -2-phenylpropanamide, a serotonin 1A receptor antagonist. MKC-242 (0.1-0.5 mg/kg, p.o.) also increased social interaction under high light and unfamiliar conditions in rats. It had weak benzodiazepine-like side effects in mice. MKC-242 (1, 3 mg/kg, p.o.) attenuated the reduction of locomotion caused by restraint stress in rats, the same effects were observed on both buspirone (100 mg/kg, p.o.) and Tandospirone (100 mg/kg, p.o.). In the forced swimming test in rats, MKC-242 (0.3-3 mg/kg, i.p.), 8-hydroxy-2-(di-n-propylamino) tetralin (1, 3 mg/kg, i.p.) and amitriptyline (30 mg/kg, i.p.) reduced immobility, although diazepam, buspirone and Tandospirone did not. The reduction by MKC-242 and 8-OH-DPAT was antagonized by N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl) -2-phenylpropanamide. Moreover, the reduction was also blocked by 1-(2--pyrimidinyl)piperazine (1-PP), a common metabolite of buspirone and Tandospirone. These findings suggest that MKC-242 possesses potent anxiolytic and antidepressant properties that are mediated via an activation of serotonin 1A receptors.

Kenichi Saito - One of the best experts on this subject based on the ideXlab platform.

  • Effect of 5-[3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242), a novel 5-HT1A-receptor agonist, on aggressive behavior and marble burying behavior in mice.
    Japanese Journal of Pharmacology, 2019
    Co-Authors: Hiroshi Nakai, Reiko Tabata, Kenichi Saito, Mitsuo Egawa
    Abstract:

    Abstract Behavioral effects of 5-{3-[((2S)-l,4-benzodioxan-2-ylmethyl)amino]propoxy}-l,3-benzodioxole HC1 (MKC-242), a novel 5-HT1A-receptor agonist, were evaluated using animal models of anxiety and obsessive compulsive disorder and compared against reference compounds. MKC-242 suppressed foot shock-induced fighting behavior without loss of motor coordination in mice as the reference compounds did. The ED50 values of MKC-242, buspirone, Tandospirone and diazepam were 1.7, 42, 80 and 2.0 mg/kg, p.o., respectively. The duration of the suppression of fighting by MKC-242 was longer than those of buspirone and Tandospirone and comparable to that of diazepam. Similar results were also obtained with the water-lick conflict test in rats. The plasma concentration of MKC-242 in rats was much higher than the reported value of buspirone during 0.25-6 hr after oral administration. In addition, MKC-242 reduced marble burying behavior without reduction of motor activity. Fluoxetine, Tandospirone and diazepam also reduced the behavior at non-sedative doses. These findings indicate that MKC-242 possesses a longer-lasting anxiolytic effect than azapirones. This might be due to the high concentration of the compound in plasma. In addition, it is also suggested that MKC-242 possesses an antiobsessional effect.

  • novel benzodioxan derivative 5 3 2s 1 4 benzodioxan 2 ylmethyl amino propoxy 1 3 benzodioxole hcl mkc 242 with anxiolytic like and antidepressant like effects in animal models
    Journal of Pharmacology and Experimental Therapeutics, 1996
    Co-Authors: M Abe, Kenichi Saito, R Tabata, Toshio Matsuda, A Baba, M Egawa
    Abstract:

    Behavioral effects of MKC-242 (5-{3-[((2>)-1,4-benzodioxan-2-ylmethyl)amino] propoxy}-1,3-benzodioxole CHl), a novel and selective serotonin 1A receptor agonist, were investigated in rats and mice and compared against those of diazepam, buspirone and Tandospirone. MKC-242 (0.0625-0.25 mg/kg, p.o.) significantly increased punished drinking in water-deprived rats. The reference compounds also increased punished drinking at doses of 10 to 40 mg/kg, p.o. The increase by MKC-242 was blocked by N-tert-butyl-3-(4-(2-methoxypenyl)piperazin-1-yl) -2-phenylpropanamide, a serotonin 1A receptor antagonist. MKC-242 (0.1-0.5 mg/kg, p.o.) also increased social interaction under high light and unfamiliar conditions in rats. It had weak benzodiazepine-like side effects in mice. MKC-242 (1, 3 mg/kg, p.o.) attenuated the reduction of locomotion caused by restraint stress in rats, the same effects were observed on both buspirone (100 mg/kg, p.o.) and Tandospirone (100 mg/kg, p.o.). In the forced swimming test in rats, MKC-242 (0.3-3 mg/kg, i.p.), 8-hydroxy-2-(di-n-propylamino) tetralin (1, 3 mg/kg, i.p.) and amitriptyline (30 mg/kg, i.p.) reduced immobility, although diazepam, buspirone and Tandospirone did not. The reduction by MKC-242 and 8-OH-DPAT was antagonized by N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl) -2-phenylpropanamide. Moreover, the reduction was also blocked by 1-(2--pyrimidinyl)piperazine (1-PP), a common metabolite of buspirone and Tandospirone. These findings suggest that MKC-242 possesses potent anxiolytic and antidepressant properties that are mediated via an activation of serotonin 1A receptors.