LP-211 is a brain penetrant selective agonist for the serotonin 5-HT7 receptor

被引：72

作者：

Hedlund, Peter B. ^{[1
]}

Leopoldo, Marcello ^{[2
]}

Caccia, Silvio ^{[3
]}

Sarkisyan, Gor ^{[1
]}

Fracasso, Claudia ^{[3
]}

Martelli, Giuliana ^{[3
]}

Lacivita, Enza ^{[2
]}

Berardi, Francesco ^{[2
]}

Perrone, Roberto ^{[2
]}

机构：

[1] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA

[2] Univ Bari, Dipartimento Farmacochim, I-70125 Bari, Italy

[3] Ist Ric Farmacol Mario Negri, I-20156 Milan, Italy

来源：

NEUROSCIENCE LETTERS | 2010年 / 481卷 / 01期

关键词：

Serotonin; 5-HT7; receptor; Agonist; LP-211; RA-7; Brain distribution; Body temperature; KNOCKOUT MICE; ANTAGONIST; CYCLASE; BINDING;

D O I：

10.1016/j.neulet.2010.06.036

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

We have determined the pharmacological profile of the new serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211) Radioligand binding assays were performed on a panel of 5-HT receptor subtypes The compound was also evaluated in vivo by examining its effect on body temperature regulation in mice lacking the 5-HT7 receptor (5-HT7-/-) and their 5-HT7+/+ sibling controls Disposition studies were performed in mice of both genotypes. It was found that LP-211 was brain penetrant and underwent metabolic degradation to 1-(2-diphenyl)piperazine (RA-7). In vitro binding assays revealed that RA-7 possessed higher 5-HT7 receptor affinity than LP-211 and a better selectivity profile over a panel of 5-HT receptor subtypes. In vivo it was demonstrated that LP-211, and to a lesser degree RA-7, induced hypothermia in 5-HT7+/+ but not in 5-HT7-/- mice. Our results suggest that LP-211 can be used as a 5-HT7 receptor agonist in vivo. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

引用

页码：12 / 16

页数：5

共 24 条

[1] Effects of 5-HT1A receptor antagonists on hippocampal 5-hydroxytryptamine levels: (S)-WAY100135, but not WAY100635, has partial agonist properties
Assie, MB
Koek, W
[J]. EUROPEAN JOURNAL OF PHARMACOLOGY, 1996, 304 (1-3) : 15 - 21
[2] BARD JA, 1993, J BIOL CHEM, V268, P23422
[3] MOLECULAR-BIOLOGY OF 5-HT RECEPTORS
BOESS, FG
MARTIN, IL
[J]. NEUROPHARMACOLOGY, 1994, 33 (3-4) : 275 - 317
[4] Radioligand binding analysis of knockout mice reveals 5-hydroxytryptamine7 receptor distribution and uncovers 8-hydroxy-2-(di-N-propylamino)tetralin interaction with α2 adrenergic receptors
Bonaventure, P
Nepomuceno, D
Hein, L
Sutcliffe, JG
Lovenberg, T
Hedlund, PB
[J]. NEUROSCIENCE, 2004, 124 (04) : 901 - 911
[5] 5-HT7 receptor activation inhibits mechanical hypersensitivity secondary to capsaicin sensitization in mice
Brenchat, Alex
Romero, Luz
Garcia, Monica
Pujol, Marta
Burgueno, Javier
Torrens, Antoni
Hamon, Michel
Manuel Baeyens, Jose
Buschmann, Helmut
Zamanillo, Daniel
Miguel Vela, Jose
[J]. PAIN, 2009, 141 (03) : 239 - 247
[6] Caccia S, 2007, CURR DRUG METAB, V8, P612
[7] Pindolol-insensitive [3H]-5-hydroxytryptamine binding in the rat hypothalamus;: identity with 5-hydroxytryptamine7 receptors
Clemett, DA
Kendall, DA
Cockett, MI
Marsden, CA
Fone, KCF
[J]. BRITISH JOURNAL OF PHARMACOLOGY, 1999, 127 (01) : 236 - 242
[8] 5-HT7 receptor stimulation by 8-OH-DPAT counteracts the impairing effect of 5-HT1A receptor stimulation on contextual learning in mice
Eriksson, Therese M.
Golkar, Armita
Ekstrom, Joanna C.
Svenningsson, Per
Ogren, Sven Ove
[J]. EUROPEAN JOURNAL OF PHARMACOLOGY, 2008, 596 (1-3) : 107 - 110
[9] SB-656104-A:: A novel 5-HT7 receptor antagonist with improved in vivo properties
Forbes, IT
Douglas, S
Gribble, AD
Ife, RJ
Lightfoot, AP
Garner, AE
Riley, GJ
Jeffrey, P
Stevens, AJ
Stean, TO
Thomas, DR
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (22) : 3341 - 3344
[10] A receptor autoradiographic and in situ hybridization analysis of the distribution of the 5-ht(7) receptor in rat brain
Gustafson, EL
Durkin, MM
Bard, JA
Zgombick, J
Branchek, TA
[J]. BRITISH JOURNAL OF PHARMACOLOGY, 1996, 117 (04) : 657 - 666

← 1 2 3 →