RT Journal Article
T1 The arylpiperazine derivatives<i>N</i>‐(4‐cyanophenylmethyl)‐4‐(2‐diphenyl)‐1‐piperazinehexanamide and<i>N</i>‐benzyl‐4‐(2‐diphenyl)‐1‐piperazinehexanamide exert a long‐lasting inhibition of human serotonin 5‐HT<sub>7</sub>receptor binding and<scp>cAMP</scp>signaling
A1 Atanes Juiz, Patricio
A1 Lacivita, Enza
A1 Rodríguez, Javier
A1 Brea Floriani, José Manuel
A1 Burgueño, Javier
A1 Vela, José Miguel
A1 Cadavid Torres, Isabel
A1 Loza García, María Isabel
A1 Leopoldo, Marcello
A1 Castro Pérez, María de los Ángeles
K1 3 H]-SB-269970 binding
K1 Arylpiperazine derivative
K1 cAMP signaling
K1 HEK293 cells
K1 Insurmountable antagonism
K1 Irreversible inhibition
K1 Long-lasting inhibition
K1 LP-211
K1 Preincubation/washout experiments
K1 Schild analysis
K1 Serotonin 5-HT7 receptors
AB We performed a detailed in vitro pharmacological characterization of two arylpiperazine derivatives, compound N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211) previously identified as a high-affinity brain penetrant ligand for 5-hydroxytryptamine (serotonin) type 7 (5-HT7) receptors, and its analog N-benzyl-4-(2-diphenyl)-1-piperazinehexanamide (MEL-9). Both ligands exhibited competitive displacement of [3H]-(2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine ([3H]-SB-269970) radioligand binding and insurmountable antagonism of 5-carboxamidotryptamine (5-CT)-stimulated cyclic adenosine monophosphate (cAMP) signaling in human embryonic kidney (HEK293) cells stably expressing human 5-HT7 receptors. They also inhibited forskolin-stimulated adenylate cyclase activity in 5-HT7-expressing HEK293 cells but not in the parental cell line. The compounds elicited long-lasting (at least 24 h) concentration-dependent inhibition of radioligand binding at 5-HT7-binding sites in whole-cell radioligand binding assays, after pretreatment of the cells with the compounds and subsequent compound removal. In cAMP assays, pretreatment of cells with the compounds rendered 5-HT7 receptors unresponsive to 5-CT and also rendered 5-HT7-expressing HEK293 cells unresponsive to forskolin. Compound 1-(2-biphenyl)piperazine (RA-7), a known active metabolite of LP-211 present in vivo, was able to partially inhibit 5-HT7 radioligand binding in a long-lasting irreversible manner. Hence, LP-211 and MEL-9 were identified as high-affinity long-acting inhibitors of human 5-HT7 receptor binding and function in cell lines. The detailed in vitro characterization of these two pharmacological tools targeting 5-HT7 receptors may benefit the study of 5-HT7 receptor function and it may lead to the development of novel selective pharmacological tools with defined functional properties at 5-HT7 receptors
PB Wiley
YR 2013
FD 2013-12-05
LK https://hdl.handle.net/10347/44640
UL https://hdl.handle.net/10347/44640
LA eng
NO Atanes, P., Lacivita, E., Rodríguez, J., Brea; J., Burgueño, J., Vela, J. M., Cadavid, M. I., Loza, M. I., Leopoldo, M. & Castro, M. The arylpiperazine derivatives N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide and N-benzyl-4-(2-diphenyl)-1-piperazinehexanamide exert a long-lasting inhibition of human serotonin 5-HT7 receptor binding and cAMP signaling. In: Pharmacology Research and Perspectives, 1(2), 2013
NO XUNTA de Galicia. Grant Number: 10PXIB203056PR
NO Ministerio de Economía y Competitividad. Grant Number: SAF2009-13609-C04-01
DS Minerva
RD 8 jun 2026