TY - JOUR
T1 - Design, synthesis and in vitro evaluation of bridgehead fluoromethyl analogs of N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635) for the 5-HT(1A) receptor
AU - Al Hussainy, Rana
AU - Verbeek, Joost
AU - van der Born, Dion
AU - Booij, Jan
AU - Herscheid, J. Koos D. M.
PY - 2011
Y1 - 2011
N2 - Fluorinated analogs that are related to the 5-hydroxytryptamine (5-HT(1A)) antagonist, N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635), have been synthesized and their binding affinity for the 5-HT(1A) receptor and other neurotransmitter receptors (adrenoceptors, sigma receptors, and dopamine receptors), and serotonin transporters was examined in vitro. These ligands were designed to provide a possible potential positron emission tomography (PET) ligand with high metabolic stability. To this end, the cyclohexyl moiety in WAY-100635 and in O-desmethyl WAY-100635 was replaced by a bridge-fused ring (BFR) such as adamantyl, cubyl, bicyclo[2.2.2]octyl and bicyclo[2.2.1]heptyl to reduce the metabolic rate of the amide bond hydrolysis, while a fluoromethyl group was introduced on the other bridgehead of the BFR to prevent defluorination by HF elimination. All synthesized analogs displayed high affinity in the (sub)nanomolar range for the 5-HT(1A) receptor, comparable to WAY-100635. In addition, 6b, 6c and 6d were reasonably selective to the 5-HT(1A) receptor over the above mentioned receptors. In human hepatocytes, 6b showed a suitable metabolic stability. In conclusion, the obtained data provides a promising starting point for the synthesis of the corresponding (18)F-labeled PET analogs
AB - Fluorinated analogs that are related to the 5-hydroxytryptamine (5-HT(1A)) antagonist, N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635), have been synthesized and their binding affinity for the 5-HT(1A) receptor and other neurotransmitter receptors (adrenoceptors, sigma receptors, and dopamine receptors), and serotonin transporters was examined in vitro. These ligands were designed to provide a possible potential positron emission tomography (PET) ligand with high metabolic stability. To this end, the cyclohexyl moiety in WAY-100635 and in O-desmethyl WAY-100635 was replaced by a bridge-fused ring (BFR) such as adamantyl, cubyl, bicyclo[2.2.2]octyl and bicyclo[2.2.1]heptyl to reduce the metabolic rate of the amide bond hydrolysis, while a fluoromethyl group was introduced on the other bridgehead of the BFR to prevent defluorination by HF elimination. All synthesized analogs displayed high affinity in the (sub)nanomolar range for the 5-HT(1A) receptor, comparable to WAY-100635. In addition, 6b, 6c and 6d were reasonably selective to the 5-HT(1A) receptor over the above mentioned receptors. In human hepatocytes, 6b showed a suitable metabolic stability. In conclusion, the obtained data provides a promising starting point for the synthesis of the corresponding (18)F-labeled PET analogs
U2 - https://doi.org/10.1016/j.ejmech.2011.06.023
DO - https://doi.org/10.1016/j.ejmech.2011.06.023
M3 - Article
C2 - 22000209
SN - 0223-5234
VL - 46
SP - 5728
EP - 5735
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
IS - 12
ER -