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1.
J Neurochem ; 76(1): 173-81, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11145990

ABSTRACT

Converging lines of evidence implicate the beta-amyloid peptide (Ass) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce A beta production by functionally inhibiting gamma-secretase, the activity responsible for the carboxy-terminal cleavage required for A beta production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon A beta production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APP(V717F) reduces brain levels of Ass in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain A beta in vivo. Development of such novel functional gamma-secretase inhibitors will enable a clinical examination of the A beta hypothesis that Ass peptide drives the neuropathology observed in Alzheimer's disease.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Brain/metabolism , Dipeptides/administration & dosage , Endopeptidases/metabolism , Administration, Oral , Alzheimer Disease/drug therapy , Alzheimer Disease/genetics , Amyloid Precursor Protein Secretases , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Aspartic Acid Endopeptidases , Brain/cytology , Brain/drug effects , Cells, Cultured , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Endopeptidases/drug effects , Enzyme Inhibitors/administration & dosage , Female , Humans , Injections, Subcutaneous , Kidney/cytology , Kidney/drug effects , Kidney/metabolism , Male , Mice , Mice, Transgenic , Neurons/cytology , Neurons/drug effects , Neurons/metabolism , Peptide Fragments/metabolism
2.
J Med Chem ; 39(14): 2773-80, 1996 Jul 05.
Article in English | MEDLINE | ID: mdl-8709108

ABSTRACT

A series of potent, selective 5HT2B receptor antagonists has been identified based upon yohimbine, with SAR studies resulting in a 1000-fold increase in 5HT2B receptor affinity relative to the starting structure (-log KBS > 10.0 have been obtained). These high-affinity tetrahydro-beta-carboline antagonists are able to discriminate among the 5HT2 family of serotonin receptors, with members of the series showing selectivities of more than 100-fold versus both the 5HT2A and 5HT2C receptors based upon radioligand binding and functional assays. As the first compounds reported with such selectivity and enhanced receptor affinity, these tetrahydro-beta-carboline antagonists are useful tools for elucidating the role of serotonin acting at the 5HT2B receptor in normal and disease physiology.


Subject(s)
Carbolines/pharmacology , Muscle, Smooth/drug effects , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Animals , Carbolines/chemical synthesis , Cell Line , Cricetinae , Gastric Fundus , In Vitro Techniques , Male , Mesocricetus , Mice , Molecular Structure , Muscle Contraction/drug effects , Rats , Rats, Wistar , Receptor, Serotonin, 5-HT2A , Receptor, Serotonin, 5-HT2B , Receptor, Serotonin, 5-HT2C , Receptors, Serotonin/genetics , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Structure-Activity Relationship , Yohimbine/chemistry
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