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Research ArticleArticle

Interaction of Tryptamine and Ergoline Compounds with Threonine 196 in the Ligand Binding Site of the 5-Hydroxytryptamine6 Receptor

Frank G. Boess, Frederick J. Monsma Jr., Valerie Meyer, Catherine Zwingelstein and Andrew J. Sleight
Molecular Pharmacology September 1997, 52 (3) 515-523; DOI: https://doi.org/10.1124/mol.52.3.515
Frank G. Boess
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland
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Frederick J. Monsma Jr.
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland
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Valerie Meyer
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland
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Catherine Zwingelstein
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland
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Andrew J. Sleight
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland
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Abstract

We examined the ligand-binding site of the 5-hydroxytryptamine6 (5-HT6) receptor using site-directed mutagenesis. Interactions with residues in two characteristic positions of transmembrane region V are important for ligand binding in several bioamine receptors. In the 5-HT6receptor, one of these residues is a threonine (Thr196), whereas in most other mammalian 5-HT receptors, the corresponding residue is alanine. After transient expression in human embryonic kidney 293 cells, we determined the effects of the mutation T196A on [3H]d-lysergic acid diethylamide (LSD) binding and adenylyl cyclase stimulation. This mutation produced a receptor with a 10-fold reduced affinity for [3H]LSD and a 6-fold reduced affinity for 5-HT. The potency of both LSD and 5-HT for stimulation of adenylyl cyclase was also reduced by 18- and 7-fold, respectively. The affinity of other N1-unsubstituted ergolines (e.g., ergotamine, lisuride) was reduced 10–30-fold, whereas the affinity of N1-methylated ergolines (e.g., metergoline, methysergide, mesulergine) and other ligands, such as methiothepine, clozapine, ritanserin, amitriptyline, and mianserin, changed very little or increased. This indicates that in wild-type 5-HT6 receptor, Thr196 interacts with the N1 of N1-unsubstituted ergolines and tryptamines, probably forming a hydrogen bond. Based on molecular modeling, a serine residue in transmembrane region IV of the 5-HT2A receptor has previously been proposed to interact with the N1-position of 5-HT. When the corresponding residue of the 5-HT6 receptor (Ala154) was converted to serine, no change in the affinity of twelve 5-HT6 receptor ligands or in the potency of 5-HT and LSD could be detected, suggesting that this position does not contribute to the ligand binding site of the 5-HT6 receptor.

Footnotes

    • Received March 14, 1997.
    • Accepted May 19, 1997.
  • Send reprint requests to: Dr. Frank G. Boess, Department PRPN, 70/343, F. Hoffmann-La Roche AG, Postfach, CH-4070 Basel, Switzerland. E-mail: frank.boess{at}roche.com

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 52 (3)
Molecular Pharmacology
Vol. 52, Issue 3
1 Sep 1997
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Research ArticleArticle

Interaction of Tryptamine and Ergoline Compounds with Threonine 196 in the Ligand Binding Site of the 5-Hydroxytryptamine6 Receptor

Frank G. Boess, Frederick J. Monsma, Valerie Meyer, Catherine Zwingelstein and Andrew J. Sleight
Molecular Pharmacology September 1, 1997, 52 (3) 515-523; DOI: https://doi.org/10.1124/mol.52.3.515

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Research ArticleArticle

Interaction of Tryptamine and Ergoline Compounds with Threonine 196 in the Ligand Binding Site of the 5-Hydroxytryptamine6 Receptor

Frank G. Boess, Frederick J. Monsma, Valerie Meyer, Catherine Zwingelstein and Andrew J. Sleight
Molecular Pharmacology September 1, 1997, 52 (3) 515-523; DOI: https://doi.org/10.1124/mol.52.3.515
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