MCPP but not TFMPP is an antagonist at cardiac 5HT3 receptors

doi:10.1016/0024-3205(92)90372-V

Life Sciences

Volume 50, Issue 8, 1992, Pages 599-605

https://doi.org/10.1016/0024-3205(92)90372-V Get rights and content

Abstract

The prototypic arylpiperazines, $meta$ -chlorophenylpiperazine (mCPP), $meta$ -trifluoromethylphenylpiperazine (TFMPP) and quipazine are widely studied serotonergic ligands with nonselective effects at 5HT₁ and 5HT₂ receptor subtypes. The present study was designed to compare the affinities of these arylpiperazines at 5HT₃ receptors, and to determine agonist or antagonist activity at 5HT₃ receptors. Quipazine showed high affinity at brain 5HT₃ receptors (IC₅₀ = 4.4 nM) and was a potent agonist of the von Bezold-Jarisch reflex in anesthetized rats, a response mediated by cardiac 5HT₃ receptors. In concentrations that activated 5HT₃ receptors, quipazine also antagonized serotonin-induced bradycardia in anesthetized rats. Taken together, these data suggest that quipazine is an agonist/antagonist with high affinity at 5HT₃ receptors in both brain and cardiac tissue. Although mCPP also showed relatively high affinity at brain 5HT₃ receptors (IC₅₀ = 61.4 nM), it did not activate the von Bezold-Jarisch reflex; instead, mCPP potently antagonized serotonin-induced bradycardia. Thus, mCPP acts as an antagonist at 5HT₃ receptors in the periphery. Although both quipazine and mCPP possessed relatively high affinity at brain 5HT₃ receptors, TFMPP did not bind appreciably to 5HT₃ receptors in brain (IC₅₀ = 2373 nM) and neither activated nor inhibited cardiac 5HT₃ receptors. That TFMPP did not interact with 5HT₃ receptors, whereas quipazine and mCPP did, is in marked contrast to the similar effects of all three arylpiperazines at other serotonin receptors. The selectivity of TFMPP for 5HT₁ and 5HT₂ receptors (i.e., its minimal affinity for 5HT₃ receptors) suggests that this arylpiperazine may be a preferred ligand relative to mCPP when studying 5HT₁ or 5HT₂ receptor mediated responses.

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Citation Excerpt :
TFMPP, a serotonin-mimicking piperazine, blocks serotonin reuptake, enhances serotonin release and is a nonselective agonist at serotonin receptors (Nikolova and Danchev, 2008). TFMPP does not possess significant noradrenergic actions (Fantegrossi et al., 2005; Herndon et al., 1992), but rather binds to 5-HT1 and 5-HT2 receptors with little affinity for 5-HT3 receptors (Baumann et al., 2005; Cunningham and Appel, 1986; Robertson et al., 1992). Baumann et al. (2005) observed MDMA-like dopamine and 5-HT release in BZP/TFMPP treated mice (Baumann et al., 2005).
Designer drugs are synthetic structural analogues/congeners of controlled substances with slightly modified chemical structures intended to mimic the pharmacological effects of known drugs of abuse so as to evade drug classification. Benzylpiperazine (BZP), a piperazine derivative, elevates synaptic dopamine and serotonin levels producing stimulatory and hallucinogenic effects, respectively, similar to the well-known drug of abuse, methylenedioxymethamphetamine (MDMA). Furthermore, BZP augments the release of norepinephrine by inhibiting presynaptic autoreceptors, therefore, BZP is a “messy drug” due to its multifaceted regulation of synaptic monoamine neurotransmitters. Initially, pharmaceutical companies used BZP as a therapeutic drug for the treatment of various disease states, but due to its contraindications and abuse potential it was withdrawn from the market. BZP imparts predominately sympathomimetic effects accompanied by serious cardiovascular implications. Addictive properties of BZP include behavioral sensitization, cross sensitization, conditioned place preference and repeated self-administration. Additional testing of piperazine derived drugs is needed due to a scarcity of toxicological data and widely abuse worldwide.
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2000, European Journal of Pharmacology
Many antipsychotics have marked antagonist effects at 5-hydroxytryptamine (5-HT_2C) receptors in vitro, which, however, have been difficult to show in behavioral assays. Here, we used two assays — hypolocomotion and hypophagia induced by the 5-HT_2C receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) — to try to characterize the 5-HT_2C receptor antagonist properties of antipsychotics in vivo. Clozapine, olanzapine, pipamperone, and trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz-[2,3:6,7]oxepino[4,5-C] pyrrolidino maleate (ORG 5222), modestly, but significantly, attenuated mCPP (10 mg/kg)-induced hypolocomotion. In contrast, risperidone and loxapine were inactive. The putative antipsychotic ORG 5222 significantly attenuated mCPP (5 mg/kg)-induced hypophagia, whereas the other antipsychotics were inactive. Selective antagonists at dopamine D₂-like receptors, α₁-adrenoceptors, α₂-adrenoceptors, or muscarinic receptors were not able to antagonize the effects of mCPP in either assay. The results suggest that mCPP-induced hypolocomotion can be used to characterize the 5-HT_2C receptor antagonist properties of antipsychotics, whereas mCPP-induced hypophagia appeared to be sensitive only to compounds highly selective for 5-HT_2C receptors. Together, these assays may help to characterize functional, in vivo, 5-HT_2C receptor antagonist properties of antipsychotics.
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While homomers containing 5-HT_3A subunits form functional ligand-gated serotonin (5-HT) receptors in heterologous expression systems (Jackson, M. B., and Yakel, J. L. (1995) Annu. Rev. Physiol. 57, 447–468; Lambert, J. J., Peters, J. A., and Hope, A. G. (1995) in Ligand-Voltage-Gated Ion Channels (North, R., ed) pp. 177–211, CRC Press, Inc., Boca Raton, FL), it has been proposed that native receptors may exist as heteromers (Fletcher, S., and Barnes, N. M. (1998) Trends Pharmacol. Sci. 19, 212–215). We report the cloning of a subunit 5-HT_3B with ∼44% amino acid identity to 5-HT_3A that specifically modified 5-HT_3Areceptor kinetics, voltage dependence, and pharmacology. Co-expression of 5-HT_3B with 5-HT_3A modified the duration of 5-HT₃ receptor agonist-induced responses, linearized the current-voltage relationship, increased agonist and antagonist affinity, and reduced cooperativity between subunits. Reverse transcriptase-polymerase chain reaction in situhybridization revealed co-localization of both 5-HT_3B and 5-HT_3A in a population of neurons in the amygdala, telencephalon, and entorhinal cortex. Furthermore, 5-HT_3Aand 5-HT_3B mRNAs were expressed in spleen and intestine. Our data suggest that 5-HT_3B might contribute to tissue-specific functional changes in 5-HT₃-mediated signaling and/or modulation.

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MCPP but not TFMPP is an antagonist at cardiac 5HT3 receptors

Abstract

Life Sci.

Neuropharm.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Life Sci.

MCPP but not TFMPP is an antagonist at cardiac 5HT₃ receptors