Structural combination of established 5-HT(2A) receptor ligands: new aspects of the binding mode

TY - JOUR

T1 - Structural combination of established 5-HT(2A) receptor ligands: new aspects of the binding mode

AU - Kramer, Vasko

AU - Herth, Matthias M

AU - Santini, Martin A

AU - Palner, Mikael

AU - Knudsen, Gitte M

AU - Rösch, Frank

N1 - © 2010 John Wiley & Sons A/S.

PY - 2010/10/1

Y1 - 2010/10/1

N2 - MH.MZ, MDL 100907, and altanserin are structurally similar 4-benzoyl-piperidine derivatives and are well accommodated to receptor interaction models. We combined structural elements of different high-affinity and selective 5-HT2A antagonists, as MH.MZ, altanserin, and SR 46349B, to improve the binding properties of new compounds. Three new derivatives were synthesized with a 4-benzoyl-piperidine moiety as the lead structure. The in vitro affinity of the novel compounds was determined by a [3H]MDL 100907 competition binding assay. The combination of MH.MZ and SR 46349B resulted in a compound (8) with a moderate affinity toward the 5-HT2A receptor (Ki = 57 nm). The remarkably reduced affinity of other compounds (4a), (4b), and (4c) (Ki = 411, 360 and 356 nm respectively) indicates that MH.MZ can only bind to the 5-HT2A receptor with the p-fluorophenylethyl residue in a sterically restricted hydrophobic binding pocket.

AB - MH.MZ, MDL 100907, and altanserin are structurally similar 4-benzoyl-piperidine derivatives and are well accommodated to receptor interaction models. We combined structural elements of different high-affinity and selective 5-HT2A antagonists, as MH.MZ, altanserin, and SR 46349B, to improve the binding properties of new compounds. Three new derivatives were synthesized with a 4-benzoyl-piperidine moiety as the lead structure. The in vitro affinity of the novel compounds was determined by a [3H]MDL 100907 competition binding assay. The combination of MH.MZ and SR 46349B resulted in a compound (8) with a moderate affinity toward the 5-HT2A receptor (Ki = 57 nm). The remarkably reduced affinity of other compounds (4a), (4b), and (4c) (Ki = 411, 360 and 356 nm respectively) indicates that MH.MZ can only bind to the 5-HT2A receptor with the p-fluorophenylethyl residue in a sterically restricted hydrophobic binding pocket.

KW - Binding, Competitive

KW - Combinatorial Chemistry Techniques

KW - Fluorobenzenes

KW - Hydrophobic and Hydrophilic Interactions

KW - Ketanserin

KW - Ligands

KW - Phenols

KW - Piperidines

KW - Protein Binding

KW - Pyridines

KW - Receptor, Serotonin, 5-HT2A

KW - Serotonin 5-HT2 Receptor Antagonists

U2 - 10.1111/j.1747-0285.2010.01011.x

DO - 10.1111/j.1747-0285.2010.01011.x

M3 - Journal article

C2 - 20636331

SN - 1747-0277

VL - 76

SP - 361

EP - 366

JO - Chemical Biology and Drug Design (Print)

JF - Chemical Biology and Drug Design (Print)

IS - 4

ER -