The α2-adrenoceptor antagonist activity of ipsapirone and gepirone is mediated by their common metabolite 1-(2-pyrimidinyl)-piperazine (PmP)

Bianchi, Giancarlo; Caccia, Silvio; Vedova, Franco Della; Garattini, Silvio

doi:10.1016/0014-2999(88)90532-8

Cited by 66 publications

(12 citation statements)

References 15 publications

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“…However, these 5-HT,A-receptor agonists act not only at 5-HT,A receptors but also at other sites; for example, buspirone, gepirone and ipsapirone markedly increase the turnover rate of dopamine (DA) in rat brain in a 5-HT,A-receptor-independent mechanism (8). In addition, a metabolite of azapirones, 1-(2-pyrimidyl)piperazine, exhibits potent a2-adrenoceptor antagonistic properties (9,10) and exerts opposite effects to those associated with the stimulation of 5-HT,A receptors (11). These findings argue against the hypothesis that 5-HT,A receptors may be a molecular target for the nonbenzodiazepine anxiolytics.…”

mentioning

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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mentioning

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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“…The rise in plasma 1PP 1 h after the last dose was also different (F(l,ll) taking ipsapirone (Figure 4). Table 1 [3][4][5][6] which has anxiogenic-like effects [25], seems to counteract the antidepressive properties of buspirone [26], and antagonises the effect of clonidine in different animal models [4,5]. Formation of IPP after ipsapirone has been found to be smaller than with buspirone [12] although no direct comparison has been made.…”

Section: Resultsmentioning

confidence: 99%

“…The azapirones buspirone, ipsapirone, gepirone and tandospirone have a common pharmacologically active metabolite the 1-(2-pyrimidinyl)-piperazine (IPP) [3][4][5][6] resulting from oxidative dealkylation of the parent compounds [7]. 1PP has a2-adrenoceptor antagonist activity in different animal models [4,5,8].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the alpha 2‐adrenoceptor blocking properties of buspirone and ipsapirone in healthy subjects. Relationship with the plasma concentration of the common metabolite 1‐(2‐pyrimidinyl)‐piperazine.

Berlin

Chalon

Payan

et al. 1995

Brit J Clinical Pharma

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1 Because the 5-HTlA agonist anxiolytic azapirones have a common a2-adrenoceptor antagonist metabolite, 1-(2-pyrimidinyl)-piperazine (IPP), we measured central and peripheral a2-adrenoceptor dependent responses before and after intravenous administration of 0.15 mg clonidine when healthy subjects were taking buspirone (30 mg day-1 for 4 days and 10 mg on day 5), ipsapirone (15 mg day-'for 4 days and 5 mg on day 5) or placebo. 2 Clonidine decreased blood pressure, heart rate, oral body temperature, salivary excretion, plasma noradrenaline, 3,4-dihydroxyphenylglycol (DHPG) concentrations, increased plasma growth hormone but did not modify plasma insulin and C-peptide concentrations. Treatments tended to modify only the effect of clonidine on growth hormone (P = 0.07). 3 The azapirones reduced clonidine induced prolongation of choice reaction time (P = 0.015) and tended to antagonise clonidine induced fall in critical flicker fusion frequency (P = 0.066). 4 Only buspirone reduced total reaction time and increased critical flicker fusion threshold measured 12 h after the evening dose and these effects were correlated with the residual plasma lPP concentration which was higher on buspirone than on ipsapirone (2.76 ,ug 1-1, 95% CI:1.3-4.22 vs 0.65 ,ug I1-, 95% CI: 0.32-0.98, P = 0.006). 5 Mean AUC of the IPP plasma concentrations after the last dose of treatments were 3.7 times greater with buspirone than with ipsapirone (P = 0.0011). The AUC ipsapirone/AUC IPP ratio was 6.45 and the AUC buspirone/AUC lPP ratio was 0.076. 6 The formation of the common metabolite IPP is greater with buspirone than with ipsapirone. Buspirone but not ipsapirone (both given in therapeutically equivalent doses) exerted a psychostimulatory effect and this could be attributed to the higher plasma lPP concentrations found with buspirone. 7 A clearcut antagonism of clonidine actions by IPP could not be demonstrated probably because the ratio of the exogeneous a2-adrenoceptor agonist (clonidine) to the endogenously formed a2-adrenoceptor antagonist (1 PP) could not be controlled.

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“…In addition, azapirones are rapidly metabolized into 1-(2-pyrimidinyl)-piperazine (1-PP) which is an alpha-2 adrenoreceptor antagonist, like mirtazapine [134,151] an effective antidepressant drug. However, the antidepressantlike effect of 1-PP is not well established [131,152,153].…”

Section: -Ht 1a Receptor Agonists In Major Depressionmentioning

confidence: 99%

Partial Dopamine D2/Serotonin 5-HT1A Receptor Agonists as New Therapeutic Agents~!2009-12-17~!2010-04-07~!2010-07-20~!

Etiévant¹

2010

TONEUROPPJ

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Abstract:The therapeutic efficacy of current antipsychotic or antidepressant agents still present important drawbacks such as delayed onset of action and a high percentage of non-responders. Despite significant advancements in the development of new drugs with more acceptable side-effect profiles, patients with schizophrenia or major depression experience substantial disability and burden of disease. The present review discusses the usefulness of partial dopamine D 2 /serotonin 5-HT 1A receptors agonists in the treatment of schizophrenia, major depression and bipolar disorder as well as in Parkinson's disease. Partial agonists can behave as modulators since their intrinsic activity or efficacy of a partial agonist depends on the target receptor population and the local concentrations of the natural neurotransmitter. Thus, these drugs may restore adequate neurotransmission while inducing less side effects. In schizophrenia, partial DA D 2 /5-HT 1A receptor agonists (like aripiprazole or bifeprunox), by stabilizing DA system via a preferential reduction of phasic DA release, reduce side effects i.e. extrapyramidal symptoms and improve cognition by acting on 5-HT 1A receptors. Aripiprazole appears also as a promising agent for the treatment of depression since it potentiates the effect of SSRIs in resistant treatment depression. Concerning bipolar disorders aripiprazole may have only a benefit effect in the treatment of manic episodes. Conversely, treatment of Parkinson's disease with partial DA D 2 /5-HT 1A receptor agonists remains still experimental. However several studies suggest that these drugs decrease usually observed side effects (dyskinesia, psychoticlike symptoms) in Parkinson's disease treatment. Hence, these relatively recent researches provide an exciting future in the discovery of novel stabilizators agents for the management of the latter diseases.

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The α2-adrenoceptor antagonist activity of ipsapirone and gepirone is mediated by their common metabolite 1-(2-pyrimidinyl)-piperazine (PmP)

Cited by 66 publications

References 15 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

Evaluation of the alpha 2‐adrenoceptor blocking properties of buspirone and ipsapirone in healthy subjects. Relationship with the plasma concentration of the common metabolite 1‐(2‐pyrimidinyl)‐piperazine.

Partial Dopamine D2/Serotonin 5-HT1A Receptor Agonists as New Therapeutic Agents~!2009-12-17~!2010-04-07~!2010-07-20~!

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