National Institutes of Health, a Component of the US Dept. of Health & Human Services

The United States of America As Represented by the Department of Health

Research Triangle Institute

Southern Research Institute

University of Arizona

University of Iowa Research Foundation

University of New England College of Osteopathic Medicine

Office of Technology Transfer

Richard B Rothman

Subramaniam Ananthan

Bruce Edward Blough

Kenner C Rice

Brian R De Costa

Michael J Iadarola

Edward J Bilsky

Frank Porreca

Samuel W Mascarella

Karen F Berman

Ann Decker

Frank Ivy Carroll

Thomas Prisinzano

Kevin M Page

Frank J Carroll

John R Glowa

Dorota Matecka

Antonio Landavazo

David Lewis

The disclosure provides monoamine neurotransmitter releaser and/or monoamine uptake inhibitor compounds having biogenic amine transporter activity but lacking substantial activity at 5-HTreceptor subtypes. The phenethylamine or vinylogous phenethylamine compounds of the disclosure are useful in treating diseases, conditions and/or disorders mediated by activity of one or more of the monoamine neurotransmitters.

Vinylogous phenethylamines as neurotransmitter releasers

The present disclosure relates to certain amine derivatives of fused bicyclic heterocycles that inhibit the amine reuptake function of the biogenic amine transporters, dopamine transporter (DAT), serotonin transporter (SERT) and norepinephrine transporter (NET). Compounds of the present disclosure are potent inhibitors of the reuptake of dopamine (DA), serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) with full or partial maximal efficacy. The compounds with partial maximal efficacy in inhibiting reuptake of all three biogenic amines are herein referred to as partial triple uptake inhibitors (PTRIs). Compounds of the present disclosure are useful for treating depression, pain and substance abuse and relapse to substance abuse and addiction to substances such as cocaine, methamphetamine, nicotine and alcohol. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Quinazolines as biogenic amine transport modulators

Heterocyclic compounds as biogenic amine transport modulators

Provided herein are compounds and prodrugs and methods of preparation of compounds and prodrugs that are capable of functioning as releasers and/or uptake inhibitors of one or more monoamine neurotransmitters, including dopamine, serotonin, and norepinephrine. Also provided are pharmaceutical compositions comprising one or more of these compounds or prodrugs, which may further comprise one or more additional therapeutic agents. Also provided are methods of treatment of various conditions that may be responsive to modification of monoamine neurotransmitter levels, such as pre-obesity, obesity, addiction, and depression.

Phenylmorpholines and analogues thereof

Compounds represented by the formula: wherein R is Calkyl; Ccycloalkylalkyl; or Calkenyl; R' is H or Calkyl; X is H or OH; Y is alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl or aroyl; and Z is CH or N; provided that X is H, when Z is CH and R is Ccycloalkylalkyl or Calkenyl; prodrugs thereof; and pharmaceutically acceptable salts thereof are provided. Compounds of the above formula are useful as analgesics for treating pain; as immunomodulators, to modulate the behavioral effects of drugs of abuse and to modulate the development of tolerance and dependence to &#x3bc; agonists.

Pyridomorphinans, pyridazinomorphinans and use thereof

The invention provides novel compounds of formula I: that are opioid receptor ligands. The invention also provides pharmaceutical compositions comprising such compounds as well as methods for treating diseases associated with opioid receptor function by administering such compounds to a mammal in need of treatment. The invention also provides an improved method for isolating intermediate materials useful for obtaining compounds of formula I.

Opioid receptor ligands and methods for their preparation

The present invention provides sustained-release derivatives of hydroxylated analogs of substituted 1-&lsqb;2&lsqb;bis(aryl)methoxy&rsqb;ethyl&rsqb;-piperazines and -homopiperazines, pharmaceutical compositions comprising the same, and a method of using such sustained-release derivatives to bind the dopamine transporter to achieve a desired effect, such as antagonism of dopamine reuptake inhibitors, such as cocaine, or dopamine releasers or norepinephrine and/or serotonin reuptake inhibitors, such as methamphetamine.

Sustained-release derivatives of hydroxylated analogs of substituted 1-&lsqb;2&lsqb;bis(aryl)methoxy&rsqb;ethyl&rsqb;-piperazines and -homopiperazines and their use

The present invention provides a compound having the structure: ##STR1## wherein X, Y, and Z are independently H, Cl, Br, F, OCH.sub.3, I, or an alkyl group having 1 to 6 carbon atoms; and R is ##STR2## wherein n is 0 to 6, X' and Y' are independently H, Cl, F, CH.sub.3, C.sub.2 H.sub.5, C.sub.3 H.sub.7, C.sub.4 H.sub.9, OCH.sub.3, OH, CF.sub.3, OCF.sub.3, NO.sub.2, NH.sub.2, N(CH.sub.3).sub.2, NHCOCH.sub.3, NCS, NHCOCH.sub.2 Br, or N.sub.3, and (CH.sub.2).sub.n, if present, may be substituted with OH, OCH.sub.3, or an alkyl or alkenyl group having 1 to 3 carbon atoms. The present invention also provides a pharmaceutical composition comprising the compound above and a pharmaceutically acceptable carrier. The present invention further provides a method for treating a disease characterized by a dopamine deficiency which comprises administering to a subject in need of such treatment an amount of the pharmaceutical composition above effective to treat the disease.

Selective inhibitors of biogenic amine transporters

The present invention is directed to radiolabeled N-substituted-6-iodo-3,14-dihydroxy-4,5.alpha.-epoxymorphinans, intermediates for producing the same, and a process for the preparation and methods of detecting opioid receptors. The radioimaging agent of the present invention has the following formula: ##STR1## wherein I is selected from the group consisting of .sup.123 L and .sup.125 ; and where R is alkyl, cycloalkylloweralkyl or allyl.

Radiolabeled n-substituted-6-iodo-3,14-dihydroxy-4,

The present invention is directed to radiolabeled N-substituted-6-iodo-3,14-dihydroxy-4,5.alpha.-epoxymorphinans, intermediates for producing the same, and a process for the preparation and methods of detecting opioid receptors. The radioimaging agent of the present invention has the following formula: ##STR1## wherein I is selected from the group consisting of .sup.123 I and .sup.125 I; and where R is alkyl, cycloalkylloweralkyl or allyl.

Radiolabeled

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Richard B Rothman