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Design, synthesis and evaluation of amino-anilino-pyramidines as potential spect ligands for the CRF1 receptor
S31
Poster Abstracts
DESIGN, SYNTHESIS AND EVALUATION OF AMINO-ANTLINO-PYRIMIDINES LIGANDS FOR THE CRFl RECEPTOR. Laurent Martarellol*,
AS POTENTIAL SPECT
Clinton D. Kilts2. Timothy Ely2, Michael J. 0wens2. Charles B. Nemeroffz and Mark M.
Goodman 1 lDepartment of Radiology, 2Department of Psychiatry, Emory Center for Positron Emission Tomography, Emory university of Medicine, 1364 Clifton Road N.E., Atlanta, GA 30322 USA Corticotropin-releasing endocrine, autonomic psychiatq
factor (CRF) has been widely repotted to play a major role in coodinating the
and behavioral response to stress. Given clinical studies implicating
a role for CRF in
illness, efforts have been focused on the design of lipophillic drugs that may penetrate the blood-brain-
barrier and be bioavailable in the brain. Recently Neurocrine Biosciences Inc. reported the synthesis of a series of amino-aniline-pyrimidines of [I-125]Tyf’-o-CRF
that demonsaated high aftinity for CRFl receptor (Ki= 4.1 nM for inhibiting the binding
to rat membrane). In order to obtain a promising SPECT radioligand for the CRFl receptor.
we investigated the substitution of the 2,4,6-hichloroaniline anilines. We synthesized
two candidates;
group of the parent molecule (1) by different iodinated-
2,6-dichloro-4-iodo-anilino
(2) and 2,6-dimethyl-4-iodo-anilino
(3)
derivatives for in vitro binding studies in rat cerebellum homogenates. They both exhibited nearly identical affinity (respectively 4.04 nM and 4.7 nM) as the parent molecule (4.1 nM) and an order of magnitude greater potency than CRF (45.4). Details of the synthesis, radiolabeling and the brain biodisbibution in rats will be presented. CORTICOSTEROIB RECEFTORS INDUCED BY RESTRUNT
(MR AND GR) MODULAlX
TBE ANXIOGENIC-LIKE
BEHAVIOR
Nelson C&o. Silvia Kademian and Marta Volosin* Department of Pharmacology, School of Chemical Sciences, CQdoba National University, Ciudad Univcrsitaria, 5000 C6rdoh Argentina. In previous studies we have shown that male rats cxposad to a 1S-min restraint period, exhibited 24 h later, an ax&g&c-like response in the elevated plus-maze, which was reversed by metyrapoue, a cuticosteroue (CORT) synthesis inhibitor, injected 3h before to the stress event. Given that CORT binds to two central axtiwsteroid receptcq minerrdocorticoid receptors @Its) and glucounticoid raxptors (GRs), we have examined the role of MRs and GRs in &is behavioral response induced by restraint. Administration of the GR agonist dexamethasone (IIF& 1.25p&g sc) 1 h before rtit in metyrapone (75 mgikg ip) pretreated rats rc&ored the auxiog~ic-like behavior induced by stress. A CORT dose (2.5 m@g SC) that a&at= both h4Rs and GRs did not modify metyrapcne effect. Adrmaleaomy (ADX) reversed the auiog&like reqoase, sub&h&u either with a low (0.125 mg/kg sc; predominant MRs ocuqatiou) ox with a high (2.5 q/kg SC)Dee of CORT was unable to pmdify the ADX effect. In amtrast, the selective activation of MRs by replacunent with deoxycutiaxt~one (WC, 0.8 mg/kg sc ) or of the GRs by DEX restored the auxiogcmic e&t. Inbncc&roventrioula infusion, 15 miu before restraint, to iutact animals of specific GRs (RU 38486) or MRs (RU 28318) autag~ists (100 ngi2pl), abolished stress-induced behavioral response. Lie ADX, the cc&&d blockade ofMR and OR revemed tbe restmint e&t. These results demonstrate that the enhanced anxiety observed following the exposure to a brief restraint event is mediated, at least in part , by the activation of MRs and GRs and suggest a probable rol of these sites in the longterm arnsequeuces of stress.
Poster Abstracts
DESIGN, SYNTHESIS AND EVALUATION OF AMINO-ANTLINO-PYRIMIDINES LIGANDS FOR THE CRFl RECEPTOR. Laurent Martarellol*,
AS POTENTIAL SPECT
Clinton D. Kilts2. Timothy Ely2, Michael J. 0wens2. Charles B. Nemeroffz and Mark M.
Goodman 1 lDepartment of Radiology, 2Department of Psychiatry, Emory Center for Positron Emission Tomography, Emory university of Medicine, 1364 Clifton Road N.E., Atlanta, GA 30322 USA Corticotropin-releasing endocrine, autonomic psychiatq
factor (CRF) has been widely repotted to play a major role in coodinating the
and behavioral response to stress. Given clinical studies implicating
a role for CRF in
illness, efforts have been focused on the design of lipophillic drugs that may penetrate the blood-brain-
barrier and be bioavailable in the brain. Recently Neurocrine Biosciences Inc. reported the synthesis of a series of amino-aniline-pyrimidines of [I-125]Tyf’-o-CRF
that demonsaated high aftinity for CRFl receptor (Ki= 4.1 nM for inhibiting the binding
to rat membrane). In order to obtain a promising SPECT radioligand for the CRFl receptor.
we investigated the substitution of the 2,4,6-hichloroaniline anilines. We synthesized
two candidates;
group of the parent molecule (1) by different iodinated-
2,6-dichloro-4-iodo-anilino
(2) and 2,6-dimethyl-4-iodo-anilino
(3)
derivatives for in vitro binding studies in rat cerebellum homogenates. They both exhibited nearly identical affinity (respectively 4.04 nM and 4.7 nM) as the parent molecule (4.1 nM) and an order of magnitude greater potency than CRF (45.4). Details of the synthesis, radiolabeling and the brain biodisbibution in rats will be presented. CORTICOSTEROIB RECEFTORS INDUCED BY RESTRUNT
(MR AND GR) MODULAlX
TBE ANXIOGENIC-LIKE
BEHAVIOR
Nelson C&o. Silvia Kademian and Marta Volosin* Department of Pharmacology, School of Chemical Sciences, CQdoba National University, Ciudad Univcrsitaria, 5000 C6rdoh Argentina. In previous studies we have shown that male rats cxposad to a 1S-min restraint period, exhibited 24 h later, an ax&g&c-like response in the elevated plus-maze, which was reversed by metyrapoue, a cuticosteroue (CORT) synthesis inhibitor, injected 3h before to the stress event. Given that CORT binds to two central axtiwsteroid receptcq minerrdocorticoid receptors @Its) and glucounticoid raxptors (GRs), we have examined the role of MRs and GRs in &is behavioral response induced by restraint. Administration of the GR agonist dexamethasone (IIF& 1.25p&g sc) 1 h before rtit in metyrapone (75 mgikg ip) pretreated rats rc&ored the auxiog~ic-like behavior induced by stress. A CORT dose (2.5 m@g SC) that a&at= both h4Rs and GRs did not modify metyrapcne effect. Adrmaleaomy (ADX) reversed the auiog&like reqoase, sub&h&u either with a low (0.125 mg/kg sc; predominant MRs ocuqatiou) ox with a high (2.5 q/kg SC)Dee of CORT was unable to pmdify the ADX effect. In amtrast, the selective activation of MRs by replacunent with deoxycutiaxt~one (WC, 0.8 mg/kg sc ) or of the GRs by DEX restored the auxiogcmic e&t. Inbncc&roventrioula infusion, 15 miu before restraint, to iutact animals of specific GRs (RU 38486) or MRs (RU 28318) autag~ists (100 ngi2pl), abolished stress-induced behavioral response. Lie ADX, the cc&&d blockade ofMR and OR revemed tbe restmint e&t. These results demonstrate that the enhanced anxiety observed following the exposure to a brief restraint event is mediated, at least in part , by the activation of MRs and GRs and suggest a probable rol of these sites in the longterm arnsequeuces of stress.