Duke University

Emory University

Oregon Health & Science University

Molecular Devices Corporation

Sanford-burnham Medical Research Institute

Universidade Federal De Minas Gerais

Marc G Caron

Lawrence S Barak

Robert J Lefkowitz

Raul R Gainetdinov

Robert H Oakley

Stephen S Ferguson

Jie Zhang

Klim King

Martin Beaulieu

Stephane Alain Laporte

Henrik G Dohlman

Tatiana D Sotnikova

Randy D Blakely

Tatyana D Sotnikova

Robert T Fremeau, Jr

Xiaodong Zhang

Bruno Giros

Jeffrey L Benovic

Ranga R Krishnan

Jacob P R Jacobsen

Martin J Lohse

Mohamed Jaber

Keith R Jarvie

Mario Tiberi

Sébastien Marion

Anthony B Pinkerton

Olivier Civelli

David K Grandy

James R Bunzow

David M Gooden

Paul M Hershberger

Patrick R Maloney

Michael P Hedrick

Satyamaheshwar Peddibhotla

David A Schwartz

Alyson M Wilbanks

Thomas Pack

Dewey G McCafferty

Julie A Pollock

Redford B Williams

Larry S Barak

Qun Y Zhou

Sudarshan Rajagopal

Lauranell Burch

Vania F Prado

Michael A Shetzline

Marco A Prado

Raul R Gainetdinova

Grace S Pereira

Braulio M Castro

Henrick G Dohlman

Jeffrey Smith

Cristina M Silva

Ivan A Izquierdo

Laura M Bohn

Fang-Tsyr Lin

Allen Dearry

Pierre Falardeau

Jay A Gingrich

Susanna Cotecchia

Lee F Allen

Lawrence Barak

Jacob PR Jacobsen

Provided are methods for detecting protein interactions in a sample, the methods comprising: (a) detecting two or more polypeptides that when associated emit a first detectable signal in a first light emission spectrum; (b) contacting the two or more polypeptides with a third polypeptide conjugated to a dipole acceptor moiety that has a second light emission spectrum when excited within a light excitation spectrum, wherein the light excitation spectrum overlaps with the first light emission spectrum; and (c) detecting a second detectable signal emitted in the second light emission spectrum by the dipole acceptor moiety. Also provided are bioluminescent complexes comprising: (a) a first polypeptide conjugated to a dipole acceptor moiety, wherein the emits a first detectable signal in a first light emission spectrum.

Complex BRET technique for measuring biological interactions

Provided are methods of enhancing bioavailability of enterally administered 5-hydroxytryptophan (5-HTP) in a subject in need thereof, said method comprising enterally co-administering low-dose carbidopa with said 5-HTP, as well as pharmaceutical formulations useful for the same. In some embodiments, the 5-HTP and/or low-dose carbidopa are provided as slow-release formulation(s).

Compositions and methods of enhancing 5-hydroxytryptophan bioavailability

Provided herein are small molecule neurotensin receptor agonists, compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.

Small molecule agonists of neurotensin receptor 1

The present invention is directed to a method of treating Parkinson's disease using arylcyclopropylamine compounds. The arylcyclopropylamine compounds have the following formula wherein R, R, R, R, Rand Rare described herein.

Methods of treatment using arylcyclopropylamine compounds

The present invention concerns the treatment of serotonergic dysregulation disorders and/or augmentation of serotonin levels in the brain by add-on treatments to serotonin enhancers, and slow-release formulations of 5-hydroxytryptophan (5-HTP) therefor.

Slow-release formulations of 5-hydroxytryptophan as an adjunct to pro-serotonergic therapies

Recombinant non-human mammals having reduced or no expression of vesicular acetylcholine transporter protein (VAChT) as compared to the corresponding wild-type mammal are provided. The mammal may have, e.g., impaired performance in object and social recognition and/or impaired neuromuscular performance and/or alterations in autonomic nervous system function as compared to the corresponding wild-type mammal. Methods of screening a compound for cholinergic activity or activity in treating a cholinergic neurotransmission disorder are also provided. In addition, a cell such as a nerve cell isolated from a mammal as described herein is provided, along with cell cultures, which are useful in vitro for screening the activity of candidate compounds for their effect on cholinergic neurotransmission, and for their activity in treating cholinergic neurotransmission disorders.

Mouse model of cholinergic dysfunction to evaluate cognitive enhancers and drugs that improve myasthenia

A method of treating a subject for Parkinson's disease comprises administering said subject a phenylisopropylamine in an amount effective to treat said Parkinson's disease. In some embodiments the method is used to treat at least a motor symptom of Parkinson's disease; in some embodiments the method is used to treat at least a non-motor symptom of Parkinson's disease.

Antiparkinsonian action of phenylisopropylamines

Recombinant or transgenic non-human mammals are described having a mutant tryptophan hydroxylase 2 (Tph2) gene resulting in altered synthesis of 5-hydroxytryptophan and serotonin in the brain. In some embodiments the mutant tryptophan hydroxylase 2 gene contains mouse R439H and/or P447R functional mutations, or their corresponding mutations in other species. Congenic non-human mammals having mutant tryptophan hydroxylase 2 genes are also provided. Methods of screening a compound for serotonergic activity or activity in treating a serotonergic neurotransmission dysregulation disorder are provided, which include administering a test compound to a recombinant non-human mammal and then detecting the presence or absence of serotonergic activity, or activity in treating a serotonergic neurotransmission dysregulation disorder, in the mammal. A cell such as a nerve cell (e.g., a central nervous system neuron) isolated from a transgenic or congenic mammal is also disclosed, along with cell cultures containing these cells.

Transgenic mice carrying functional single nucleotide polymorphisms in brain-specific tryptophan hydroxylase

A method of screening a candidate compound for &#x3b2;Arrestin mediated anti-G protein coupled receptor signaling activity is comprises: (a) contacting said candidate compound to a &#x3b2;Arrestin signaling complex or a constituent thereof, under conditions in which a signaling complex is formed; and then (b) detecting the presence or absence of disruption of said signaling complex, disruption of said complex indicating said compound has &#x3b2;Arrestin mediated anti-G protein coupled receptor signaling activity. Compositions and kits for carrying out the method are also described.

Methods for identifying compounds that regulate beta-arrestin signaling complexes

Methods for identifying compounds that regulate &#x3b2;-Arrestin signaling complexes

A method of screening a subject for a serotonergic neurotransmission dysregulation disorder comprises detecting the presence or absence of an Tph2 mutation in the subject; and then determining that the subject is at increased risk of a serotonergic neurotransmission dysregulation disorder due to the presence or absence of the Tph2 mutation.

Polymorphism in tryptophan hydroxylase-2 controls brain serotonin synthesis

Described are methods of detecting G-protein coupled receptor (GPCR) activity in vivo and in vitro; methods of assaying GPCR activity; and methods of screening for GPCR ligands, G protein-coupled receptor kinase (GRK) activity, and compounds that interact with components of the GPCR regulatory process. Constructs useful in such methods are described.

Methods of assaying receptor activity and constructs useful in such methods

The present invention is related to the detection of GPCR ligands in a test sample by using a single cell biosensor expressing a GPCR. Preferably, the test sample is derived from a biological or environmental sample. This invention may be used to detect the presence of a disease or to detect the presence of a harmful agent in the environment. Included in the present invention is an array of biosensors that detect ligands of various GPCRs.

Single-cell biosensor for the measurement of GPCR ligands in a test sample

A method of treating a subject for a serotonergic neurotransmission dysregulation disorder, comprises administering the subject a serotonin enhancer (e.g., a serotonin reuptake inhibitor) in an amount effective to treat the disorder; and concurrently administering the subject 5-hydroxytryptophan in an amount effective to enhance the activity of the serotonin enahancer, (e.g., serotonin reuptake inhibitor). In preferred embodiments the disorder is depression, anxiety, or substance abuse.

Method for augmenting the effects of serotonin reuptake inhibitors

Disclosed is a transformed yeast cell containing a first heterologous DNA sequence which codes for a mammalian G protein-coupled receptor and a second heterologous DNA sequence which codes for a mammalian G protein &#x3b1; subunit (mammalian G). The first and second heterologous DNA sequences are capable of expression in the cell, but the cell is incapable of expressing an endogenous G protein &#x3b1;-subunit (yeast G). The cells are useful for screening compounds which affect the rate of dissociation of Gfrom Gin a cell. Also disclosed is a novel DNA expression vector useful for making cells as described above. The vector contains a first segment comprising at least a fragment of the extreme amino-terminal coding sequence of a yeast G protein-coupled receptor. A second segment is positioned downstream from the first segment (and in correct reading frame therewith), with the second segment comprising a DNA sequence encoding a heterologous G protein-coupled receptor.

Expression of G protein coupled receptors in yeast

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Hillsborough, NC, United States of America

Marc G Caron