Synthesis and Evaluation of Cyclic Diamino Benzamide Based D3 Receptor Ligands

Abstract Dopamine (1) is a key neurotransmitter whose impact on pharmacological processes is mediated by a family of dopamine receptors designated D1, D2, D3, D4, and D5. Various diseases and conditions such as schizophrenia, drug abuse, depression, restless leg syndrome, Parkinson’s disease (PD), and inflammatory diseases have been linked to aberrant D3 activity. Herein, we report a series of novel D3 ligands with improved solubility over our previous lead compound, MC25-41 (2).

Download Full-text

Dopamine D3 Receptor Ligand Suppresses the Expression of Levodopa-Induced Dyskinesia in Nonhuman Primate Model of Parkinson's Disease

10.21203/rs.3.rs-617879/v1 ◽

2021 ◽

Author(s):

Thomas Oh ◽

Elyas Daadi ◽

Jeffrey Kim ◽

Etienne Daadi ◽

Peng-Jen Chen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Partial Agonist ◽

Nigrostriatal System ◽

Dopamine D3 Receptor ◽

D3 Receptor ◽

Lead Compound ◽

Primate Model ◽

Medical Needs ◽

Dopamine D3

Abstract Parkinson’s disease (PD) is a complex multisystem, chronic and so far incurable disease with significant unmet medical needs. The incidence of PD increases with aging and the expected burden will continue to escalate with our aging population. Since its discovery in the 1961 levodopa remains the gold standard pharmacotherapy for PD. However, the progressive nature of the neurodegenerative process in and beyond the nigrostriatal system causes a multitude of side effects, including levodopa-induced dyskinesia within 5 years of therapy. Attenuating dyskinesia has been a significant challenge in the clinical management of PD. We report on a small molecule that eliminates the expression of levodopa-induced dyskinesia and significantly improves PD-like symptoms. The lead compound PD13R we discovered is a dopamine D3 receptor partial agonist with high affinity and selectivity, orally active and with desirable drug-like properties. Future studies are aimed at developing this lead compound for treating PD patients with dyskinesia.

Download Full-text

Dopamine D3 Receptor Ligand Suppresses the Expression of Levodopa-Induced Dyskinesia in Nonhuman Primate Model of Parkinson's Disease

10.1101/2021.08.10.455884 ◽

2021 ◽

Author(s):

Thomas Oh ◽

Elyas S. Daadi ◽

Jeffrey Kim ◽

Etienne W. Daadi ◽

Peng-Jen Chen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Partial Agonist ◽

Nigrostriatal System ◽

Dopamine D3 Receptor ◽

D3 Receptor ◽

Lead Compound ◽

Primate Model ◽

Medical Needs ◽

Dopamine D3

Parkinson's disease (PD) is a complex multisystem, chronic and so far incurable disease with significant unmet medical needs. The incidence of PD increases with aging and the expected burden will continue to escalate with our aging population. Since its discovery in the 1961 levodopa remains the gold standard pharmacotherapy for PD. However, the progressive nature of the neurodegenerative process in and beyond the nigrostriatal system causes a multitude of side effects, including levodopa-induced dyskinesia within 5 years of therapy. Attenuating dyskinesia has been a significant challenge in the clinical management of PD. We report on a small molecule that eliminates the expression of levodopa-induced dyskinesia and significantly improves PD-like symptoms. The lead compound PD13R we discovered is a dopamine D3 receptor partial agonist with high affinity and selectivity, orally active and with desirable drug-like properties. Future studies are aimed at developing this lead compound for treating PD patients with dyskinesia.

Download Full-text

Dopamine Uptake Sites and Dopamine Receptors in Parkinson’s Disease and Schizophrenia

European Neurology ◽

10.1159/000117168 ◽

1990 ◽

Vol 30 (1) ◽

pp. 9-14 ◽

Cited By ~ 48

Author(s):

R.K.B. Pearce ◽

P. Seeman ◽

K. Jellinger ◽

W. Tourtellotte

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopamine Receptors ◽

Dopamine Uptake ◽

Dopamine Uptake Sites ◽

Uptake Sites

Download Full-text

An Exploratory Retrospective Evaluation of Ropinirole-Associated Psychotic Symptoms in an Outpatient Population Treated for Restless Legs Syndrome or Parkinson's Disease

Annals of Pharmacotherapy ◽

10.1345/aph.1m183 ◽

2009 ◽

Vol 43 (9) ◽

pp. 1426-1432 ◽

Cited By ~ 10

Author(s):

Steven C Stoner ◽

Megan M Dahmen ◽

Mignon Makos ◽

Jessica W Lea ◽

Lora J Carver ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopamine Receptors ◽

Restless Legs Syndrome ◽

Dopamine Agonists ◽

Dual Therapy ◽

Psychotic Symptoms ◽

Antipsychotic Treatment ◽

Restless Legs ◽

Psychotic Features

Background: Traditional treatment approaches for the management of restless legs syndrome (RLS) and Parkinson's disease (PD) include the use of medications that either directly or indirectly increase dopamine levels. In turn, a potential adverse event that could be expected is the development or exacerbation of psychiatric-related symptoms. Objective: To evaluate and describe the incidence of psychosis and associated behavioral features in patients taking ropinirole for RLS or PD. Methods: Patients were identified from a computerized database search of outpatients being treated with ropinirole for 1 of 2 medical conditions: PD or RLS. Data were collected in a retrospective manner from 95 patients who were tracked over the course of their therapy to determine whether psychosis or associated behavioral symptoms developed as a result and whether an intervention was needed to adjust ropinirole dosing or if additional medications had to be added to control features associated with psychosis. Results: A total of 284 patients being treated for RLS or PD were identified; of this group, 95 patients were identified as being treated for PD or RLS with ropinirole. Of the 95 patients being treated with ropinirole, 13 developed psychotic features that required therapeutic intervention with either the use of an antipsychotic or dose adjustment of ropinirole. PD patients included in this study were numerically more likely to develop psychotic features compared with RLS patients; however, the difference was not statistically significant (p = 0.122). The results do suggest that this risk is increased when ropinirole is used as part of a dual therapy approach with dopamine agonists in the treatment of either PD or RLS (p = 0.003). Discussion: Dopamine agonists have long been used as preferred treatment in the management of PD and RLS. When treating either PD or RLS in the psychiatric population, the concern arises that increased activity at dopamine receptors may induce or exacerbate psychiatric features. A potential clinical concern with the use of ropinirole is the potential for patients to develop psychiatric features, although there are few data available to demonstrate whether stimulation of targeted individual dopamine receptors is linked to the development or exacerbation of psychotic features. It is also undetermined whether concurrent antipsychotic treatment provides any protective benefit against psychosis, especially in patients already being treated for psychotic symptoms. Conclusions: Our findings suggest that ropinirole may play a role in inducing or exacerbating psychosis and its associated features, although a number of confounding variables prevent the determination of a clear association and suggest that further investigation is warranted in controlled clinical trials.

Download Full-text

Cross-Sectional Design: Link Between Parkinson’s Pain and Restless Leg Syndrome

Journal of Geriatric Psychiatry and Neurology ◽

10.1177/08919887211036188 ◽

2021 ◽

pp. 089198872110361

Author(s):

Dion A. Paul ◽

Abdul Rehman Qureshi ◽

Muhammad K. Jamal ◽

Abdul Qayyum Rana

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Pain Perception ◽

Brief Pain Inventory ◽

Insufficient Evidence ◽

Restless Leg Syndrome ◽

Cross Sectional ◽

Holistic Treatment ◽

Cross Sectional Design ◽

The Relationship

Objective: Prior research suggests that restless leg syndrome (RLS) is prevalent in Parkinson’s disease (PD) with insufficient evidence to support the relationship between RLS, PD, and pain. This study explored the relationship between pain in PD patients and its association with the prevalence and severity of RLS. Method: 127 PD patients were assessed for PD and RLS using the U.K. Brain bank Criteria and the Restless Leg Syndrome diagnostic criteria, respectively. These patients were also assessed for pain perception and interference using the Brief Pain Inventory. Results: The results demonstrated Parkinson’s disease patients who reported pain scored 23 more Restless Leg Syndrome prevalence points ( p < 0.05), and 8.5 counts higher for Restless Leg Syndrome severity ( p < 0.05) compared to the group of Parkinson’s disease patients denying pain. Discussion: The presence of pain in PD patients indicated a higher RLS prevalence and an increased RLS severity. This finding suggests patients suffering from pain interference may experience more severe RLS symptoms. This demonstrates an inextricable link and association between pain in PD patients and RLS. Further robust investigations are required to elucidate any potential causative links, which can inform more holistic treatment principles.

Download Full-text

Receptor Ligands as Helping Hands to L-DOPA in the Treatment of Parkinson’s Disease

Biomolecules ◽

10.3390/biom9040142 ◽

2019 ◽

Vol 9 (4) ◽

pp. 142 ◽

Cited By ~ 6

Author(s):

Fabio Bello ◽

Mario Giannella ◽

Gianfabio Giorgioni ◽

Alessandro Piergentili ◽

Wilma Quaglia

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Side Effects ◽

Elevated Liver Enzyme ◽

Therapeutic Potential ◽

Motor Complication ◽

Receptor Ligands ◽

Dopaminergic Drugs ◽

The Many ◽

Non Motor Symptoms

Levodopa (LD) is the most effective drug in the treatment of Parkinson’s disease (PD). However, although it represents the “gold standard” of PD therapy, LD can cause side effects, including gastrointestinal and cardiovascular symptoms as well as transient elevated liver enzyme levels. Moreover, LD therapy leads to LD-induced dyskinesia (LID), a disabling motor complication that represents a major challenge for the clinical neurologist. Due to the many limitations associated with LD therapeutic use, other dopaminergic and non-dopaminergic drugs are being developed to optimize the treatment response. This review focuses on recent investigations about non-dopaminergic central nervous system (CNS) receptor ligands that have been identified to have therapeutic potential for the treatment of motor and non-motor symptoms of PD. In a different way, such agents may contribute to extending LD response and/or ameliorate LD-induced side effects.

Download Full-text