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 language | English (US) |
|---|---|
| Pages (from-to) | 2961-2970 |
| Number of pages | 10 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 54 |
| Issue number | 8 |
| DOIs | |
| State | Published - Apr 28 2011 |
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ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
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. / Donohue, Sean R.; Dannals, Robert F; Halldin, Christer; Pike, Victor W.
In: Journal of Medicinal Chemistry, Vol. 54, No. 8, 28.04.2011, p. 2961-2970.Research output: Contribution to journal › Article
}
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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U2 - 10.1021/jm2000536
DO - 10.1021/jm2000536
M3 - Article
C2 - 21428406
AN - SCOPUS:79955383737
VL - 54
SP - 2961
EP - 2970
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 8
ER -