Structurally similar small molecule photoaffinity CCK-A agonists and antagonists as novel tools for directly probing 7TM receptor-ligand interactions

被引：14

作者：

Darrow, JW ^{[2
]}

Hadac, EM

Miller, LJ

Sugg, EE

机构：

[1] Mayo Clin & Mayo Fdn, Ctr Digest Dis, Rochester, MN 55905 USA

[2] Neurogen Corp, Branford, CT 06405 USA

[3] Glaxo Wellcome Inc, Dept Med Chem, Res Triangle Pk, NC 27709 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 1998年 / 8卷 / 22期

关键词：

D O I：

10.1016/S0960-894X(98)00548-4

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Incorporation of photolabile benzoyl (2a-d) or trifluoromethyl-3H-diazirine (3a-d) substituents into 1,5-benzodiazepine ligands did not significantly impair the rat CCK-A binding affinity of either agonists or antagonists. The modified agonist ligands also retained functional potency and efficacy in the rat amylase assay. Despite their strong structural similarity, the SAR of this limited set of compounds suggests that these small molecule antagonists and agonists might differ in their mode of binding to the CCK-A receptor. Preliminary affinity results show that representative agonists and antagonists from these series can be used to efficiently covalently label the CCK-A receptor. (C) 1998 Elsevier Science Ltd. All rights reserved.

引用

收藏

页码：3127 / 3132

页数：6

相关论文

共 20 条

[1] Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity .1. Optimization of the agonist ''Trigger'' [J].

Aquino, CJ ;

Armour, DR ;

Berman, JM ;

Birkemo, LS ;

Carr, RAE ;

Croom, DK ;

Dezube, M ;

Dougherty, RW ;

Ervin, GN ;

Grizzle, MK ;

Head, JE ;

Hirst, GC ;

James, MK ;

Johnson, MF ;

Miller, LJ ;

Queen, KL ;

Rimele, TJ ;

Smith, DN ;

Sugg, EE .

JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (02) :562-569

[2]

BRUNNER J, 1980, J BIOL CHEM, V255, P3313

[3] SELECTIVE LABELING OF THE HYDROPHOBIC CORE OF MEMBRANES WITH 3-(TRIFLUOROMETHYL)-3-(M-[I-125]IODOPHENYL)DIAZIRINE, A CARBENE-GENERATING REAGENT [J].

BRUNNER, J ;

SEMENZA, G .

BIOCHEMISTRY, 1981, 20 (25) :7174-7182

[4] A NEW AND RAPID METHOD FOR CLINICAL DETERMINATION OF ALPHA-AMYLASE ACTIVITIES IN HUMAN SERUM AND URINE . OPTIMAL CONDITIONS [J].

CESKA, M ;

BIRATH, K ;

BROWN, B .

CLINICA CHIMICA ACTA, 1969, 26 (03) :437-&

[5] BENZOPHENONE PHOTOPHORES IN BIOCHEMISTRY [J].

DORMAN, G ;

PRESTWICH, GD .

BIOCHEMISTRY, 1994, 33 (19) :5661-5673

[6] DESIGN OF POTENT, ORALLY EFFECTIVE, NONPEPTIDAL ANTAGONISTS OF THE PEPTIDE-HORMONE CHOLECYSTOKININ [J].

EVANS, BE ;

BOCK, MG ;

RITTLE, KE ;

DIPARDO, RM ;

WHITTER, WL ;

VEBER, DF ;

ANDERSON, PS ;

FREIDINGER, RM .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1986, 83 (13) :4918-4922

[7]

FLEMING SA, 1995, TETRAHEDRON, V51, P12479

[8] NOVEL TOOL FOR THE STUDY OF CHOLECYSTOKININ-STIMULATED PANCREATIC-ENZYME SECRETION [J].

GAISANO, HY ;

KLUEPPELBERG, UG ;

PINON, DI ;

PFENNING, MA ;

POWERS, SP ;

MILLER, LJ .

JOURNAL OF CLINICAL INVESTIGATION, 1989, 83 (01) :321-325

[9] Direct identification of a second distinct site of contact between cholecystokinin and its receptor [J].

Hadac, EM ;

Pinon, DI ;

Ji, ZS ;

Holicky, EL ;

Henne, RM ;

Lybrand, TP ;

Miller, LJ .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (21) :12988-12993

[10] Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity .2. Optimization of the C3 amino substituent [J].

Hirst, GC ;

Aquino, C ;

Birkemo, L ;

Croom, DK ;

Dezube, M ;

Dougherty, RW ;

Ervin, GN ;

Grizzle, MK ;

Henke, B ;

James, MK ;

Johnson, MF ;

Momtahen, T ;

Queen, KL ;

Sherrill, RG ;

Szewczyk, J ;

Willson, TM ;

Sugg, EE .

JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (26) :5236-5245