Synthesis and Pharmacological Characterization of 2-(2,6-Dichlorophenyl)-1-((1S,3R)-5-(3-hydroxy-3-methylbutyl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (LY3154207), a Potent, Subtype Selective, and Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor

Hao, Junliang; Beck, James P.; Schaus, John M.; Krushinski, Joseph H.; Chen, Qi; Beadle, Christopher D.; Vidal, Paloma; Reinhard, Matthew R.; Dressman, Bruce A.; Massey, Steven M.; Boulet, Serge L.; Cohen, Michael P.; Watson, Brian M.; Tupper, David E.; Gardinier, Kevin M.; Myers, Jason K.; Johansson, Anette M.; Richardson, Jeffery; Richards, Daniel S; Hembre, Erik J.; Remick, David M.; Coates, David A.; Bhardwaj, Rajni M.; Diseroad, Benjamin A.; Bender, David M.; Stephenson, Greg A.; Wolfangel, Craig D.; Dı́az, Nuria; Getman, Brian G.; Wang, Xu-Shan; Heinz, Beverly A.; Cramer, Jeff W; Zhou, Xin; Maren, Deanna L; Falcone, Julie F.; Wright, Rebecca A.; Mitchell, Stephen N.; Carter, Guy; Yang, Charles R.; Bruns, Robert F.; Svensson, Kjell

doi:10.1021/acs.jmedchem.9b01234

Cited by 49 publications

(109 citation statements)

References 89 publications

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“…Both clinical and pre-clinical studies have demonstrated the importance of DA in MDD and specified the potential therapeutic role of the D1 agonist but limitations such as the biphasic effects of such compounds on higher cognitive functions have prevented the clinical development of any selective D1 agonist for MDD. Lately, a novel potent human D1 positive allosteric modulator, LY3154207, was identified with potential pro-cognitive effects and decreased immobility in the FST in preclinical models (Hao et al, 2019; Svensson et al, 2019). LY3154207 is currently in Phase II clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Selective activation of D1 dopamine receptors exerts antidepressant-like activity in rats

et al. 2020

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Background: Major depressive disorder is a common illness that severely decreases psychosocial functioning. Due to the major limitations of current treatments including response failure, it is crucial to develop better therapy strategies. Evidence suggests that dopamine dysregulation might play a major role in major depressive disorder physiopathology. Aims: This study investigates whether the dopamine D1 receptor agonist A77636 modulates antidepressant-like activity in rats. Methods: Rats were injected with an acute single dose of A77636 (0.75, 1.5 or 3 mg/kg), a potent and selective dopamine D1-like receptor agonist. Their locomotor activity, social interactions and behavioural response to the forced swim test were analysed 30 min after the injection. Results: During the forced swim test, the D1 agonist dose dependently reduced the immobility while the time of bursting was increased. Social interactions were significantly increased in the animals exposed to 3 mg/kg of A77636 whereas no significant changes were measured in general motor activity. Conclusions: The present results provide evidence that pharmacological modulation of D1 receptor by the selective agonist A77636 induces antidepressant-like effects in rats, which encourages further studies regarding D1-specific modulation in major depressive disorder treatment.

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Section: Discussionmentioning

confidence: 99%

Selective activation of D1 dopamine receptors exerts antidepressant-like activity in rats

et al. 2020

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“…Allosteric modulators represent an alternative and promising strategy for G protein-coupled receptor (GPCR) drug discovery with high selectivity and low side effects. Eli Lilly developed the first clinical D 1 -positive allosteric modulator (PAM), LY3154207 [ 62 , 67 , 68 ], which shows no tachyphylaxis in preclinical animal models [ 62 , 67 , 68 ]. A phase 1 trial of LY3154207 in 80 participants, including healthy participants and PD patients, which studied the safety, tolerability, and PK of multiple ascending doses, was completed in 2017 (NCT02562768).…”

Section: Updates On the Clinical Progress Of Dopaminergic Pd Treatmenmentioning

confidence: 99%

Recent advances in dopaminergic strategies for the treatment of Parkinson’s disease

et al. 2020

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s Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease worldwide. However, there is no available therapy reversing the neurodegenerative process of PD. Based on the loss of dopamine or dopaminergic dysfunction in PD patients, most of the current therapies focus on symptomatic relief to improve patient quality of life. As dopamine replacement treatment remains the most effective symptomatic pharmacotherapy for PD, herein we provide an overview of the current pharmacotherapies, summarize the clinical development status of novel dopaminergic agents, and highlight the challenge and opportunity of emerging preclinical dopaminergic approaches aimed at managing the features and progression of PD.

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“…This property can be exploited to have safer drugs to use as an adjunctive therapy for schizophrenic patients who have cognitive-resistant deficits. As a matter of fact, the novel D 1 receptor-positive allosteric modulator LY3154207 has now reached the clinic in phase 2 studies for Lewy body dementia [ 77 ]; it would be interesting in future to investigate whether it also improves cognitive symptoms in schizophrenia.…”

Section: Allosteric Modulators As a New Class Of Antipsychoticsmentioning

confidence: 99%

Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics

et al. 2020

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Schizophrenia was first described by Emil Krapelin in the 19th century as one of the major mental illnesses causing disability worldwide. Since the introduction of chlorpromazine in 1952, strategies aimed at modifying the activity of dopamine receptors have played a major role for the treatment of schizophrenia. The introduction of atypical antipsychotics with clozapine broadened the range of potential targets for the treatment of this psychiatric disease, as they also modify the activity of the serotoninergic receptors. Interestingly, all marketed drugs for schizophrenia bind to the orthosteric binding pocket of the receptor as competitive antagonists or partial agonists. In recent years, a strong effort to develop allosteric modulators as potential therapeutic agents for schizophrenia was made, mainly for the several advantages in their use. In particular, the allosteric binding sites are topographically distinct from the orthosteric pockets, and thus drugs targeting these sites have a higher degree of receptor subunit specificity. Moreover, “pure” allosteric modulators maintain the temporal and spatial fidelity of native orthosteric ligand. Furthermore, allosteric modulators have a “ceiling effect”, and their modulatory effect is saturated above certain concentrations. In this review, we summarize the progresses made in the identification of allosteric drugs for dopamine and serotonin receptors, which could lead to a new generation of atypical antipsychotics with a better profile, especially in terms of reduced side effects.

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Cited by 49 publications

References 89 publications

Selective activation of D1 dopamine receptors exerts antidepressant-like activity in rats

Selective activation of D1 dopamine receptors exerts antidepressant-like activity in rats

Recent advances in dopaminergic strategies for the treatment of Parkinson’s disease

Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics

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