N -(4-cyanotetrahydro-2 H -pyran-4-yl) and N -(1-cyanocyclohexyl) derivatives of 1,5-diarylpyrazole-3-carboxamides showing high affinity for 18 kDa translocator protein and/or cannabinoid receptors

Sean R. Donohue, Robert F Dannals, Christer Halldin, Victor W. Pike

Research output: Contribution to journalArticle

Abstract

In order to develop improved radioligands for imaging brain CB1 receptors with positron emission tomography (PET) based on rimonabant (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl) -1H-pyrazole-3-carboxamide, 1), we synthesized compounds 9a-s in which the N-piperidinyl ring was replaced with a 4-(4-cyanotetrahydro-2H-pyranyl) or 1-cyanocyclohexyl ring. Such changes were expected to be almost isosteric with 1, confer greater metabolic resistance, and in the case of the 4-(4-cyanotetrahydro-2H-pyranyl) compounds, substantially reduce lipophilicity. One derivative, 1-(2-bromophenyl)-N-(1-cyanocyclohexyl)-5-(4-methoxyphenyl)-4- methylpyrazole-3-carboxamide (9n), showed high affinity (Ki = 15.7 nM) and selectivity for binding to CB1 receptors. The corresponding 4-(4-cyanotetrahydro-2H-pyranyl) derivative (9m) also showed quite high affinity for CB1 receptors (Ki = 62 nM) but was found to have even higher affinity (Ki = 29 nM) for the structurally unrelated 18 kDa translocator protein (TSPO). Some other minor structural changes among 9a-s were also found to switch binding selectivity from CB1 receptors to TSPO or vice versa. These unexpected findings and their implications for the development of selective ligands or PET radioligands for CB1 receptors or TSPO are discussed in relation to current pharmacophore models of CB1 receptor and TSPO binding sites.

Original languageEnglish (US)
Pages (from-to)2961-2970
Number of pages10
JournalJournal of Medicinal Chemistry
Volume54
Issue number8
DOIs
StatePublished - Apr 28 2011

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Pyrans
Cannabinoid Receptor CB1
Cannabinoid Receptors
Proteins
rimonabant
Positron-Emission Tomography
Protein Binding
Neuroimaging
Binding Sites
Ligands

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

@article{571b994594ab406a8b5f690b6c052358,
title = "N -(4-cyanotetrahydro-2 H -pyran-4-yl) and N -(1-cyanocyclohexyl) derivatives of 1,5-diarylpyrazole-3-carboxamides showing high affinity for 18 kDa translocator protein and/or cannabinoid receptors",
abstract = "In order to develop improved radioligands for imaging brain CB1 receptors with positron emission tomography (PET) based on rimonabant (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl) -1H-pyrazole-3-carboxamide, 1), we synthesized compounds 9a-s in which the N-piperidinyl ring was replaced with a 4-(4-cyanotetrahydro-2H-pyranyl) or 1-cyanocyclohexyl ring. Such changes were expected to be almost isosteric with 1, confer greater metabolic resistance, and in the case of the 4-(4-cyanotetrahydro-2H-pyranyl) compounds, substantially reduce lipophilicity. One derivative, 1-(2-bromophenyl)-N-(1-cyanocyclohexyl)-5-(4-methoxyphenyl)-4- methylpyrazole-3-carboxamide (9n), showed high affinity (Ki = 15.7 nM) and selectivity for binding to CB1 receptors. The corresponding 4-(4-cyanotetrahydro-2H-pyranyl) derivative (9m) also showed quite high affinity for CB1 receptors (Ki = 62 nM) but was found to have even higher affinity (Ki = 29 nM) for the structurally unrelated 18 kDa translocator protein (TSPO). Some other minor structural changes among 9a-s were also found to switch binding selectivity from CB1 receptors to TSPO or vice versa. These unexpected findings and their implications for the development of selective ligands or PET radioligands for CB1 receptors or TSPO are discussed in relation to current pharmacophore models of CB1 receptor and TSPO binding sites.",
author = "Donohue, {Sean R.} and Dannals, {Robert F} and Christer Halldin and Pike, {Victor W.}",
year = "2011",
month = "4",
day = "28",
doi = "10.1021/jm2000536",
language = "English (US)",
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pages = "2961--2970",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
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TY - JOUR

T1 - N -(4-cyanotetrahydro-2 H -pyran-4-yl) and N -(1-cyanocyclohexyl) derivatives of 1,5-diarylpyrazole-3-carboxamides showing high affinity for 18 kDa translocator protein and/or cannabinoid receptors

AU - Donohue, Sean R.

AU - Dannals, Robert F

AU - Halldin, Christer

AU - Pike, Victor W.

PY - 2011/4/28

Y1 - 2011/4/28

N2 - In order to develop improved radioligands for imaging brain CB1 receptors with positron emission tomography (PET) based on rimonabant (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl) -1H-pyrazole-3-carboxamide, 1), we synthesized compounds 9a-s in which the N-piperidinyl ring was replaced with a 4-(4-cyanotetrahydro-2H-pyranyl) or 1-cyanocyclohexyl ring. Such changes were expected to be almost isosteric with 1, confer greater metabolic resistance, and in the case of the 4-(4-cyanotetrahydro-2H-pyranyl) compounds, substantially reduce lipophilicity. One derivative, 1-(2-bromophenyl)-N-(1-cyanocyclohexyl)-5-(4-methoxyphenyl)-4- methylpyrazole-3-carboxamide (9n), showed high affinity (Ki = 15.7 nM) and selectivity for binding to CB1 receptors. The corresponding 4-(4-cyanotetrahydro-2H-pyranyl) derivative (9m) also showed quite high affinity for CB1 receptors (Ki = 62 nM) but was found to have even higher affinity (Ki = 29 nM) for the structurally unrelated 18 kDa translocator protein (TSPO). Some other minor structural changes among 9a-s were also found to switch binding selectivity from CB1 receptors to TSPO or vice versa. These unexpected findings and their implications for the development of selective ligands or PET radioligands for CB1 receptors or TSPO are discussed in relation to current pharmacophore models of CB1 receptor and TSPO binding sites.

AB - In order to develop improved radioligands for imaging brain CB1 receptors with positron emission tomography (PET) based on rimonabant (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl) -1H-pyrazole-3-carboxamide, 1), we synthesized compounds 9a-s in which the N-piperidinyl ring was replaced with a 4-(4-cyanotetrahydro-2H-pyranyl) or 1-cyanocyclohexyl ring. Such changes were expected to be almost isosteric with 1, confer greater metabolic resistance, and in the case of the 4-(4-cyanotetrahydro-2H-pyranyl) compounds, substantially reduce lipophilicity. One derivative, 1-(2-bromophenyl)-N-(1-cyanocyclohexyl)-5-(4-methoxyphenyl)-4- methylpyrazole-3-carboxamide (9n), showed high affinity (Ki = 15.7 nM) and selectivity for binding to CB1 receptors. The corresponding 4-(4-cyanotetrahydro-2H-pyranyl) derivative (9m) also showed quite high affinity for CB1 receptors (Ki = 62 nM) but was found to have even higher affinity (Ki = 29 nM) for the structurally unrelated 18 kDa translocator protein (TSPO). Some other minor structural changes among 9a-s were also found to switch binding selectivity from CB1 receptors to TSPO or vice versa. These unexpected findings and their implications for the development of selective ligands or PET radioligands for CB1 receptors or TSPO are discussed in relation to current pharmacophore models of CB1 receptor and TSPO binding sites.

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