Review
Biochemistry & Molecular Biology
Abdeslam Chagraoui, Giuseppe Di Giovanni, Philippe De Deurwaerdere
Summary: The discovery of the D3 receptor has sparked interest in the field of neurological diseases, particularly Parkinson's disease. This article discusses the role of D3 receptors in Parkinson's disease and their relationship with current treatments, highlighting the potential interactions between D1 and D3 receptors that may contribute to motor side effects.
Article
Chemistry, Medicinal
Sabrina Biselli, Merlin Bresinsky, Katharina Tropmann, Lisa Forster, Claudia Honisch, Armin Buschauer, Gunther Bernhardt, Steffen Pockes
Summary: A series of novel H2R and D3R agonists with high affinities and selectivity have been synthesized in this study, showing promising application prospects in in vitro experiments.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Neurosciences
Jamie J. Manning, Hayley M. Green, Michelle Glass, David B. Finlay
Summary: The CB1 receptor is a promising drug target for a wide range of diseases, but existing ligands have limited therapeutic potential. Recent drug development efforts have focused on altering CB1 signaling by modulating endocannabinoid signaling or selectively targeting specific cellular pathways.
Article
Chemistry, Medicinal
Alessandro Bonifazi, Elizabeth Saab, Julie Sanchez, Antonina L. Nazarova, Saheem A. Zaidi, Khorshada Jahan, Vsevolod Katritch, Meritxell Canals, J. Robert Lane, Amy Hauck Newman
Summary: A new generation of dual-target μ opioid receptor (MOR) agonist/D3R antagonist/partial agonists was designed and synthesized. Through in vitro and in silico screening, new structural scaffolds were identified that achieved high affinity for MOR and D3R, improving receptor subtype selectivity and predicted blood-brain barrier permeability. Lead compounds have the potential for analgesic effects with reduced opioid-misuse liability via D3R antagonism.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Jacob T. Beckley, Teresa K. Aman, Michael A. Ackley, Tatiana M. Kazdoba, Michael C. Lewis, Anne C. Smith, Brandon J. Farley, Jing Dai, Wayne Deats, Ethan Hoffmann, Albert J. Robichaud, James J. Doherty, Michael C. Quirk
Summary: This study identified a neuroactive steroid NMDA receptor PAM called SAGE-718, which improves conditions associated with NMDA receptor hypofunction by increasing channel open probability.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Asher L. Brandt, Sumanta Garai, Ayat Zagzoog, Dow P. Hurst, Lesley A. Stevenson, Roger G. Pertwee, Gregory H. Imler, Patricia H. Reggio, Ganesh A. Thakur, Robert B. Laprairie
Summary: This study separates the enantiomers of CB1R positive allosteric modulators and finds that they have different biochemical activities and are related to agonist and modulator mechanisms. This provides a theoretical basis for the treatment of pain, epilepsy, glaucoma, and Huntington's disease.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Xin Lin, Nicole M. Fisher, Shalini Dogra, Rebecca K. Senter, Carson W. Reed, Jacob J. Kalbfleisch, Craig W. Lindsley, Wesley B. Asher, Zixiu Xiang, Colleen M. Niswender, Jonathan A. Javitch
Summary: The activity of hippocampal SC-CA1 synapses is regulated by mGlu(7/8) heterodimers, and different mGlu(7) NAM compounds exhibit varying activity on these heterodimers.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Irene Ramos-Alvarez, Tatiana Iordanskaia, Samuel A. Mantey, Robert T. Jensen
Summary: By studying, it is found that the nonpeptide receptor agonist MK-5046 may function as an allosteric agonist for the BRS-3 receptor, which is the first allosteric ligand described for this family of receptors. This finding is of great significance for exploring receptor function and treatment.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2022)
Article
Pharmacology & Pharmacy
Rob Hill, Andrew C. Kruegel, Jonathan A. Javitch, J. Robert Lane, Meritxell Canals
Summary: The study found differential effects of Mitragynine and its metabolite, 7-OH Mitragynine, on mouse respiration and anti-nociception. Mitragynine showed a ceiling effect on respiratory depression, while 7-OH Mitragynine had dose-dependent effects. Inhibition of CYP3A reduced the respiratory depressant effects and anti-nociception induced by Mitragynine, but had no effect on the effects of 7-OH Mitragynine. These findings suggest that metabolic saturation may contribute to the improved safety profile of Mitragynine.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Meeting Abstract
Biochemistry & Molecular Biology
Thomas M. Keck, Shreya Kelshikar, Nisha Shah, Connor McBride, Moises Ximello Sanchez, Diandra Panasis, Brianna Maslonka, Abigail Muccilli, Maria Ladik, Ebrar Akca, Sophia Ginet
Article
Biology
Alastair C. Keen, Maria Hauge Pedersen, Laura Lemel, Daniel J. Scott, Meritxell Canals, Dene R. Littler, Travis Beddoe, Yuki Ono, Lei Shi, Asuka Inoue, Jonathan A. Javitch, J. Robert Lane
Summary: Understanding the signaling of heterotrimeric G proteins is crucial for understanding physiological responses. Pertussis toxin has been widely used to inhibit G alpha(i/o) G proteins, but its effectiveness against G alpha(z) has been limited. A recently discovered toxin, OZITX, has been found to specifically inhibit both G alpha(i/o) and G alpha(z) G proteins, providing a new tool to study their signaling.
COMMUNICATIONS BIOLOGY
(2022)
Review
Pharmacology & Pharmacy
Gisela Andrea Camacho-Hernandez, Khorshada Jahan, Amy Hauck Newman
Summary: Fluorescence microscopy has revolutionized the visualization of physiological processes in live-cell systems, and with the recent innovations in super resolution microscopy, these events can be examined with high precision and accuracy. The development of fluorescently labelled small molecules has provided a significant advance in understanding the physiological relevance of targeted proteins that can now be visualized at the cellular level. The study of monoamine transporters (MATs) and their regulation and dysregulation is crucial for treating neuropsychiatric conditions, and the design of fluorescently labelled ligands (FLL) has greatly contributed to advancing our understanding of MATs in health and disease.
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
(2023)
Article
Chemistry, Medicinal
Emma S. Gogarnoiu, Caleb D. Vogt, Julie Sanchez, Alessandro Bonifazi, Elizabeth Saab, Anver Basha Shaik, Omar Soler-Cedeno, Guo-Hua Bi, Benjamin Klein, Zheng-Xiong Xi, J. Robert Lane, Amy Hauck Newman
Summary: Highly selective dopamine D3 receptor (D3R) partial agonists/antagonists have not been successful for the treatment of psychostimulant use disorders (PSUD) due to low potency/efficacy or potential cardiotoxicity. This study suggests that moderately selective D3R/D2R partial agonists/antagonists may be effective in treating PSUD and comorbidities with other affective disorders. Cariprazine and its analogues showed promising results in reducing cocaine self-administration in rats.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Omeed Rahimi, Jianjing Cao, Jenny Lam, Steven R. Childers, Rana Rais, Linda J. Porrino, Amy Hauck Newman, Michael A. Nader
Summary: Although there are currently no FDA-approved treatments for cocaine use disorder, promising results have been seen with modafinil analogs in reducing cocaine self-administration and reinstatement in rats. This study compared two compounds, JJC8-088 and JJC8-091, in rhesus monkeys and found that JJC8-088 had higher DAT affinity and showed more significant reduction in cocaine choice compared to JJC8-091. These findings suggest the potential for developing pharmacotherapeutics for cocaine use disorder without abuse liability.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2023)
Article
Pharmacology & Pharmacy
Michelle R. Doyle, Lindsey N. Peng, Jianjing Cao, Kenner C. Rice, Amy Hauck Newman, Gregory T. Collins
Summary: Despite years of research, there are currently no FDA-approved medications for treating stimulant use disorders. Preclinical studies have shown that candidate medications can reduce self-administration of stimulants in animals, but this effect is not consistently observed in humans. This may be due to the fact that most preclinical studies do not accurately replicate the dysregulated and/or compulsive drug-taking patterns seen in individuals with stimulant use disorders. However, this study found that drugs targeting dopamine D3 or 5-HT2C receptors can effectively reduce these abnormal drug-taking patterns, highlighting their potential for treating stimulant use disorders.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2023)
Review
Chemistry, Medicinal
Alessandro Bonifazi, Fabio Del Bello, Gianfabio Giorgioni, Alessandro Piergentili, Elizabeth Saab, Luca Botticelli, Carlo Cifani, Emanuela Micioni Di Bonaventura, Maria Vittoria Micioni Di Bonaventura, Wilma Quaglia
Summary: Orexin-A and Orexin-B are highly conserved hypothalamic neuropeptides that mediate their effects through two distinct G protein-coupled receptors, OX1-R and OX2-R. They play important roles in various physiological functions such as sleep-wake cycle regulation, emotion, panic-like behaviors, anxiety/stress, food intake, and energy homeostasis. This review focuses on the medicinal chemistry aspects of small molecules acting as dual or subtype selective OX1-R/OX2-R agonists and antagonists, as well as radiolabeled OX-R ligands for molecular imaging.
MEDICINAL RESEARCH REVIEWS
(2023)
Article
Neurosciences
Kendall Woodlief, Mia I. Allen, Jeremy C. Cornelissen, Matthew L. Banks, Amy Hauck Newman, Michael A. Nader
Summary: Recent studies suggest that dopamine D3 receptors (D3R) may be a therapeutic target for opioid use disorders (OUD). This study examined the effects of the D3R partial agonist (+/-)VK4-40 and the D3R-selective antagonist (+/-)VK4-116, compared to the mu-opioid receptor antagonist naltrexone (NTX), in nonhuman primate models of OUD and antinociception. The results suggest that (+/-)VK4-40 may be a novel pharmacotherapy for OUD.
NEUROPSYCHOPHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Melinda Hersey, Andy Y. Chen, Mattingly K. Bartole, Jayati Anand, Amy Hauck Newman, Gianluigi Tanda
Summary: Understanding the neurochemistry of sex differences in psychostimulant use disorders is crucial for developing effective therapies. This study utilized fast scan cyclic voltammetry to investigate dopamine dynamics in the nucleus accumbens shell of male and female mice. The findings suggest that cocaine has different effects on dopamine clearance and stimulation of the nucleus accumbens in male and female mice. Modafinil and its analogs show potential as therapeutic options for psychostimulant use disorders, with varying effects on dopamine dynamics.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Pharmacology & Pharmacy
Rob Hill, Julie Sanchez, Laura Lemel, Mirjana Antonijevic, Yselkla Hosking, Shailesh N. Mistry, Andrew C. Kruegel, Jonathan A. Javitch, J. Robert Lane, Meritxell Canals
Summary: This study evaluated the effects of three novel opioids on respiratory depression and analgesia, and compared these measurements with their in vitro efficacy. The results showed that these opioids can induce respiratory depression and analgesia at certain doses, but there are differences in potency and duration of effect among the novel opioids.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Alessandro Bonifazi, Elizabeth Saab, Julie Sanchez, Antonina L. Nazarova, Saheem A. Zaidi, Khorshada Jahan, Vsevolod Katritch, Meritxell Canals, J. Robert Lane, Amy Hauck Newman
Summary: A new generation of dual-target μ opioid receptor (MOR) agonist/D3R antagonist/partial agonists was designed and synthesized. Through in vitro and in silico screening, new structural scaffolds were identified that achieved high affinity for MOR and D3R, improving receptor subtype selectivity and predicted blood-brain barrier permeability. Lead compounds have the potential for analgesic effects with reduced opioid-misuse liability via D3R antagonism.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Luca Botticelli, Emanuela Micioni Di Bonaventura, Fabio Del Bello, Gianfabio Giorgioni, Alessandro Piergentili, Wilma Quaglia, Alessandro Bonifazi, Carlo Cifani, Maria Vittoria Micioni Di Bonaventura
Summary: Neuromedin U (NMU) is a bioactive peptide involved in multiple physiological processes, acting through two G protein coupled receptors (GPCR). NMU plays a role in regulating food intake and has anti-obesity properties. It also influences binge eating behavior, suggesting its potential as a therapeutic target for obesity and eating disorders.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Alexander Goldberg, Bing Xie, Lei Shi
Summary: The study explores the binding and allosteric mechanisms of LY3154207, an allosteric compound that targets the dopamine D1 receptor. The research provides insights into the role of LY3154207 in stabilizing the receptor structure and inducing changes in key structural motifs, contributing to the understanding of its therapeutic potential as an allosteric modulator.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Pegi Pavletic, Ana Semeano, Hideaki Yano, Alessandro Bonifazi, Gianfabio Giorgioni, Alessandro Piergentili, Wilma Quaglia, Maria Giovanna Sabbieti, Dimitrios Agas, Giorgio Santoni, Roberto Pallini, Lucia Ricci-Vitiani, Emanuela Sabato, Giulio Vistoli, Fabio Del Bello
Summary: In this paper, new ligands with high affinity and selectivity for D4R were discovered to better understand its role in GBM. The D4R antagonist 24 and biased ligand 29 showed the most potential and induced a decreased viability of GBM cells. Interestingly, these compounds had a greater effect in reducing cell viability compared to temozolomide, the first-choice chemotherapeutic drug in GBM.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)