Abstract
A series of 4'-substituted phenyl-4-piperidinylmethanol and benzoyl-4-piperidine derivatives was synthesized as potential novel serotonin 5-HT2A receptor ligands that can be radiolabeled for in vivo brain imaging. Compounds were prepared by alkylation of 4-substituted benzoyl-4-piperidine with an iodo- or fluoro-substituted phenylalkyl halide followed by reduction with sodium borohydride. Potency of novel compounds was determined by in vitro radioreceptor affinity assays selective for serotonin 5-HT2A receptors. Potent compounds were further evaluated for selectivity at serotonin-2A versus 2C, 6, and 7, as well as dopamine D2 and adrenergic alpha1 and alpha2 receptors. The novel compound (4-fluorophenyl)-(1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl])methanol was particularly promising with high 5-HT2A potency (K(i) = 1.63 nM) and >300-fold selectivity over other 5-HT receptor types.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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COS Cells
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Humans
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In Vitro Techniques
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Ligands
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / metabolism
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Prosencephalon / metabolism
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Radioligand Assay
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Rats
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Receptor, Serotonin, 5-HT2A
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Receptor, Serotonin, 5-HT2C
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Receptors, Adrenergic, alpha-1 / metabolism
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Receptors, Adrenergic, alpha-2 / metabolism
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Receptors, Dopamine D2 / metabolism
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Receptors, Serotonin / metabolism*
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Structure-Activity Relationship
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Tomography, Emission-Computed
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Tomography, Emission-Computed, Single-Photon
Substances
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(4-fluorophenyl)-(1-(2-(4-fluorophenyl)ethyl)piperidin-4-yl)methanol
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Ligands
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Piperidines
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Receptor, Serotonin, 5-HT2A
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Receptor, Serotonin, 5-HT2C
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Receptors, Adrenergic, alpha-1
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Receptors, Adrenergic, alpha-2
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Receptors, Dopamine D2
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Receptors, Serotonin
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serotonin 6 receptor
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serotonin 7 receptor