The United States of America, as Represented by the Secretary, Department of Health and Human Services

University of North Texas

US Government as Represented by the Secretary of the Army

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

Amy Hauck Newman

Jianjing Cao

Oluyomi M Okunola-Bakare

Anver Basha Shaik

Vivek Kumar

Peter Grundt

Robert R Luedtke

Frank Casper Tortella

Jonathan L Katz

Kenner C Rice

Rachel D Slack

Andrew C Allen

Richard H Kline

Mu-Fa Zou

Alessandro Bonifazi

Francisco Oscar Battiti

JoLynn Barbara Giancola

Sophie L Cemaj

Silvia N Calderon

George C Cyriac

Sari Izenwasser

Robert Leudtke

Disclosed herein are novel compounds including dopamine Dreceptor agonists, compositions thereof, methods of use thereof, and processes of synthesizing the same. Further disclosed are DR selective agonist compounds, specifically bitopic ligands comprising chirality.

D3 receptor agonist compounds; methods of preparation; intermediates thereof; and methods of use thereof

Disclosed herein novel dopamine D3 receptor selective antagonists/partial agonists compounds with high affinity and metabolic stability useful for the treatment of psychiatric and neurological disorders and as research and diagnostic tools. Also disclosed are methods of making the compounds.

Dopamine D3 receptor selective antagonists/partial agonists; method of making; and use thereof

Disclosed herein are novel methods of treating pain in a patient in need thereof by providing to the patient a selective dopamine D3 receptor antagonist/partial agonist which when used with an opioid analgesic, can mitigate the development of opioid dependence, by preventing the need for dose escalation while either maintaining the opioid analgesic effect or providing analgesia with a lower dose of the opioid. In addition, the D3 antagonists/partial agonists described herein may be used to augment the effectiveness of current Medication Assisted Treatment regimens (e.g. methadone or buprenorphine) for the treatment of opioid use disorders.

Dopamine D3 receptor selective antagonists/partial agonists and uses thereof

Disclosed herein are bisarylmethylthioacetamides and bisarylmethylthioethylamines useful as inhibitors of monoamine transporters. The compounds are potent and/or selective inhibitors of dopamine (DA), serotonin (5-HT), and/or norepinephrine (NE) reuptake via their respective transporters, DAT, SERT and NET. Also disclosed are methods for eliciting a wake-promoting or cognitive or attention enhancing effect and for treating substance use disorders, attention deficit (hyperactivity) disorder, depressive disorders, bipolar disorder or other neuropsychiatric disorders sleep disorders or cognitive impairment using the compounds.

Potent and selective inhibitors of monoamine transporters; method of making; and use thereof

Disclosed herein are a series of modafinil analogue compounds that bind with moderate to high affinity to the dopamine (DA) transporter (DAT) and several analogues also having affinity for the serotonin (5-HT) transporter (SERT) and/or sigma-1 receptor. Employing aminopiperidine, piperidineamino, spirobicyclodiaza, or substituted piperazine functional groups, desired dopamine transporter affinity has been retained along with improved metabolic stability over unsubstituted piperazine ring analogues. Importantly, these compounds have no predicted addictive liability. Also disclosed are methods for treating substance use disorders as well as other neuropsychiatric disorders such as ADHD, depression, narcolepsy, and cognitive impairment.

Atypical inhibitors of monoamine transporters; method of making; and use thereof

Dopamine Dreceptor antagonists and partial agonists are known to modulate the reinforcing and drug-seeking effects induced by cocaine and other abused substances. By introducing functionality into the butylamide linking chain of the 4-phenylpiperazine class of ligands, improved Dreceptor affinity and selectivity, as well as water solubility, is achieved. A series of linking-chain derivatives are disclosed wherein functionality such as OH or OAc groups have been introduced into the linking chain. In general, these modifications are well tolerated at Dreceptors and achieve high selectivity over Dand Dreceptors.

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Disclosed are benztropine analogs having the formula (I) in which Ar is a C-Cmonocyclic aryl group or a C-Cbicyclic aryl group or a heteroaryl, heterocyclic, or arylheterocyclic group having 2 to 12 carbon atoms and one or more heteroatoms selected from the group consisting of N, O, S, P, and any combination thereof; m=1 to 5; n=1 to 3; and Rto Rare as described in the specification; or a pharmaceutically acceptable salt or solvate thereof; pharmaceutical compositions and use thereof, e.g., in treating mental disorders. 

Benztropine compounds and uses thereof

A family of structurally rigid dopamine D3 receptor selective ligands is described. The family of structurally rigid dopamine D3 receptor selective ligands has the formula wherein A is cis or trans &#x2014;CH&#x2550;CH&#x2014;, &#x2014;C&#x2550;C&#x2014;, or cyclohexyl. B is cis or trans &#x2014;CH&#x2550;CH&#x2014; or absent. R1 represents an optionally substituted phenyl group, wherein said substituents are selected from the group consisting of: hydrogen, halogen, amino, nitro, hydroxyl, alkoxy, alkyl, acyl and pyridyl, and said substitution may occur at any of the ortho, meta, or para positions, or R1 represents a heteroaromatic ring. A preferred heteroaromatic ring is indole, quinoxoline, pyridyl, pyrimidyl, or imidazole. R2 and R3 may be independently hydrogen or a halogen, or R2 alone may be C1, C2, or C3 alkoxy, and m is 1 or 2, and n is 0, 1, or 2. 

Structurally rigid dopamine D3 receptor selective ligands and process for making them

A family of structurally rigid dopamine D3 receptor selective ligands is described. The family of structurally rigid dopamine D3 receptor selective ligands has the formula wherein A is cis or trans &#x2014;CH&#x2550;CH&#x2014;, &#x2014;C&#x2550;C&#x2014;, or cyclohexyl. B is cis or trans &#x2014;CH&#x2550;CH&#x2014; or absent. R1 represents an optionally substituted phenyl group, wherein said substituents are selected from the group consisting of: hydrogen, halogen, amino, nitro, hydroxyl, alkoxy, alkyl, acyl and pyridyl, and said substitution may occur at any of the ortho, meta, or para positions, or R1 represents a heteroaromatic ring. A preferred heteroaromatic ring is indole, quinoxoline, pyridyl, pyrimidyl, or imidazole. R2 and R3 may be independently hydrogen or a halogen, or R2 alone may be C1, C2, or C3 alkoxy, and m is 1 or 2, and n is 0, 1, or 2.

Structurally rigid dopamine d3 receptor selective ligands and process for making them

The present invention provides a family of tropane analogs. More particularly, the present invention provides a family of 4' and 4',4'-substituted-3.alpha.-(diphenylmethoxy)tropane analogs having the formula ##STR1## in which R is a functional group including, but not limited to, hydrogen, alkyl, alkoxy, arylalkyl, aryloxyalkyl, cinnamyl and acyl; and R.sup.1 and R.sup.2 are independently selected and are functional groups including, but not limited to, hydrogen, alkyl, alkoxy, hydroxy, halogen, cyano, amino and nitro. The benztropine analogs of the present invention have a high affinity for the dopamine transporter and inhibit dopamine uptake, but they do not exhibit a cocaine-like behavioral profile. Moreover, the present invention provides methods of using such benztropine analogs to treat cocaine abuse, to image dopamine transporter/cocaine binding sites, and to diagnose and/or monitor neurodegenerative disorders (e.g., Parkinson's disease). In addition, the present invention provides pharmaceutical compositions comprising a benztropine analog of the present invention and a pharmaceutically acceptable carrier or excipient.

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Phoenix, MD, United States of America

Amy Hauck Newman