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Molecular Pharmacology

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Research ArticleArticle

Position 5.46 of the serotonin 5-HT2A receptor contributes to a species-dependent variation for the 5-HT2C agonist (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one: impact on selectivity and toxicological evaluation

Keith J Miller, Ginger Y Wu, Jeffrey G Varnes, Paul Levesque, Julia Li, Danshi Li, Jeffrey A Robl, Karen A Rossi and Dean A Wacker
Molecular Pharmacology September 18, 2009, mol.109.059204; DOI: https://doi.org/10.1124/mol.109.059204
Keith J Miller
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Ginger Y Wu
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Jeffrey G Varnes
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Paul Levesque
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Julia Li
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Danshi Li
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Jeffrey A Robl
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Karen A Rossi
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Dean A Wacker
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Abstract

Successful development of 5-HT2C agonists requires selectivity vs. the highly homologous 5-HT2A receptor as agonism at this receptor can result in significant adverse events. (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (compound 1) is a potent 5-HT2C agonist exhibiting selectivity over the human 5-HT2A receptor. Evaluation of the compound at the rat 5-HT2A receptor however, revealed potent binding and agonist functional activity. The physiological consequence of this higher potency was the observation of a significant increase in blood pressure in conscious telemeterized rats, which could be prevented by ketanserin. Docking of compound 1 in a homology model of the 5-HT2A receptor indicated a possible binding mode in which the ethyl group at the 9-position of the molecule was oriented toward position 5.46 of the 5-HT2A receptor. Within the human 5-HT2A receptor position 5.46 is S242 however in the rat 5-HT2A receptor it is A242, suggesting that the potent functional activity in this species resulted from the absence of the steric bulk provided by the -OH moiety of the Ser in the human isoform. We confirmed this hypothesis utilizing site directed mutagenesis both through the mutation of the human receptor S242→A as well as the rat receptor A242→S followed by radioligand binding and second messenger studies. Additionally we attempted to define the space allowed by the alanine by evaluating compounds with larger substitutions at the 9-position. The data indicate position 5.46 contributed to the species difference in 5-HT2A receptor potency observed for a pyrazinoisoindolone compound resulting in the observation of a significant cardiovascular safety signal.

  • Serotonin
  • Gq/11 family
  • Structure-activity relationships and modeling
  • Func. analysis receptor/ion channel mutants
  • Mutagenesis/Chimeric approaches

Footnotes

    • Received July 10, 2009.
    • Revision received September 17, 2009.
    • Accepted September 17, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 99 (2)
Molecular Pharmacology
Vol. 99, Issue 2
1 Feb 2021
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Position 5.46 of the serotonin 5-HT2A receptor contributes to a species-dependent variation for the 5-HT2C agonist (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one: impact on selectivity and toxicological evaluation
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Research ArticleArticle

Position 5.46 of the serotonin 5-HT2A receptor contributes to a species-dependent variation for the 5-HT2C agonist (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one: impact on selectivity and toxicological evaluation

Keith J Miller, Ginger Y Wu, Jeffrey G Varnes, Paul Levesque, Julia Li, Danshi Li, Jeffrey A Robl, Karen A Rossi and Dean A Wacker
Molecular Pharmacology September 18, 2009, mol.109.059204; DOI: https://doi.org/10.1124/mol.109.059204

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Research ArticleArticle

Position 5.46 of the serotonin 5-HT2A receptor contributes to a species-dependent variation for the 5-HT2C agonist (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one: impact on selectivity and toxicological evaluation

Keith J Miller, Ginger Y Wu, Jeffrey G Varnes, Paul Levesque, Julia Li, Danshi Li, Jeffrey A Robl, Karen A Rossi and Dean A Wacker
Molecular Pharmacology September 18, 2009, mol.109.059204; DOI: https://doi.org/10.1124/mol.109.059204
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