Medical College of Wisconsin
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Potential modes of interaction of 9-aminomethyl-9,10-dihydroanthracene (AMDA) derivatives with the 5-HT2A receptor: a ligand structure-affinity relationship, receptor mutagenesis and receptor modeling investigation. J Med Chem 2008 Nov 13;51(21):6808-28

Date

10/14/2008

Pubmed ID

18847250

Pubmed Central ID

PMC3088499

DOI

10.1021/jm800771x

Abstract

The effects of 3-position substitution of 9-aminomethyl-9,10-dihydroanthracene (AMDA) on 5-HT 2A receptor affinity were determined and compared to a parallel series of DOB-like 1-(2,5-dimethoxyphenyl)-2-aminopropanes substituted at the 4-position. The results were interpreted within the context of 5-HT 2A receptor models that suggest that members of the DOB-like series can bind to the receptor in two distinct modes that correlate with the compounds' functional activity. Automated ligand docking and molecular dynamics suggest that all of the AMDA derivatives, the parent of which is a 5-HT 2A antagonist, bind in a fashion analogous to that for the sterically demanding antagonist DOB-like compounds. The failure of the F340 (6.52)L mutation to adversely affect the affinity of AMDA and the 3-bromo derivative is consistent with the proposed modes of orientation. Evaluation of ligand-receptor complex models suggest that a valine/threonine exchange between the 5-HT 2A and D 2 receptors may be the origin of selectivity for AMDA and two substituted derivatives.

Author List

Runyon SP, Mosier PD, Roth BL, Glennon RA, Westkaemper RB

Author

Philip Mosier PhD Assistant Professor in the School of Pharmacy Administration department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Anthracenes
Cattle
Humans
Ligands
Models, Molecular
Molecular Sequence Data
Molecular Structure
Mutagenesis
Protein Binding
Receptor, Serotonin, 5-HT2A
Sequence Alignment
Serotonin 5-HT2 Receptor Agonists
Serotonin 5-HT2 Receptor Antagonists
Structure-Activity Relationship
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a