Emergent Concepts of Receptor Pharmacology

Kenakin, Terry

doi:10.1007/164_2019_297

Cited by 12 publications

(13 citation statements)

References 111 publications

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“…These numbers alone indicate that a staggering combinatorial convergence of modulatory information must be accessible to each individual neuron (Smith et al, 2019;Taylor et al, 2021). To fully appreciate this potential information "bandwidth", one must consider not only the number of GPCR genes in play, but also that modulatory responses are graded, or "analog, " with each GPCR's agonist concentration, that subcellular GPCR localization surely matters, and that additional signaling diversity can be generated through physical and/or functional interactions when distinct GPCR protomers are co-expressed (Ferre et al, 2014;Kenakin, 2019).…”

Section: Discussionmentioning

confidence: 99%

A Molecular Landscape of Mouse Hippocampal Neuromodulation

Smith

Zastrow

2022

Front. Neural Circuits

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Adaptive neuronal circuit function requires a continual adjustment of synaptic network parameters known as “neuromodulation.” This process is now understood to be based primarily on the binding of myriad secreted “modulatory” ligands such as dopamine, serotonin and the neuropeptides to G protein-coupled receptors (GPCRs) that, in turn, regulate the function of the ion channels that establish synaptic weights and membrane excitability. Many of the basic molecular mechanisms of neuromodulation are now known, but the organization of neuromodulation at a network level is still an enigma. New single-cell RNA sequencing data and transcriptomic neurotaxonomies now offer bright new lights to shine on this critical “dark matter” of neuroscience. Here we leverage these advances to explore the cell-type-specific expression of genes encoding GPCRs, modulatory ligands, ion channels and intervening signal transduction molecules in mouse hippocampus area CA1, with the goal of revealing broad outlines of this well-studied brain structure’s neuromodulatory network architecture.

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Section: Discussionmentioning

confidence: 99%

A Molecular Landscape of Mouse Hippocampal Neuromodulation

Smith

Zastrow

2022

Front. Neural Circuits

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“…Does, e.g., propranolol fulfill the criteria of a mGPCR antagonist (Cernecka et al 2014 )? Last but not least, how can we integrate pluridimensional efficacy, biased signaling, and allosteric GPCR modulators (Hauser et al 2017 ; Seyedabadi et al 2019 ; Kenakin 2019 ) into the classification without rendering it too complicated for the physician? We hope that, with this article, we initiate a discussion at an international level that contributes to improving drug classification of, and communication about, psychotropic drugs and ultimately improves drug safety.…”

Section: Discussionmentioning

confidence: 99%

A simple mechanistic terminology of psychoactive drugs: a proposal

Seifert

Schirmer

2020

Naunyn-Schmiedeberg's Arch Pharmacol

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Antidepressants, antiepileptics, mood stabilizers, and antipsychotics are extremely broadly used psychoactive drugs. These drug terms are universally used in the literature. However, the indications of these drugs have broadened substantially and overlap. The mismatch between drug classification and clinical uses causes a lot of confusion in communication and renders literature searches increasingly difficult. Therefore, we propose to drop the above terms altogether and replace them by simple mechanistic terms. Antidepressants are re-named as norepinephrine/serotonin (NE/5-HT) enhancers, antiepileptics comprising drugs with different mechanisms become neuronal inhibitors with pleiotropic effects (NIPEs), and antipsychotics become antagonists at multiple G protein–coupled receptors (mGPCR antagonists). Alkali metal ions, comprising lithium, are integrated into NIPEs. The terms “typical/first-generation/conventional” and “atypical/second-generation/non-conventional” antipsychotics should be dropped, because the original criterion for distinction, i.e., the presence and absence of extrapyramidal motor effects, respectively, is not valid anymore. The suggested changes in drug nomenclature have already been implemented into a recent textbook (Seifert R, Basic Knowledge of Pharmacology ). The revised nomenclature ensures consistency with other fields of pharmacology and assignment of drug classes to indications without causing confusion. The authors acknowledge that the change in drug nomenclature is a cultural process that will take time and openly discuss the problems associated with the proposal. Ultimately, international learned societies will have to agree on a new nomenclature. Electronic supplementary material The online version of this article (10.1007/s00210-020-01918-x) contains supplementary material, which is available to authorized users.

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“…57 It turned recently out that the biased approach blurred the picture of agonist/antagonist. [58][59][60] Indeed, once examined with a multitude of functional assays each addressing a different pathway, agonists at this pathway could be neutral at another one or, even worse, antagonist at a third one, as in the case, for example, of the classical reference antagonists at melatonin receptors, luzindole and 4-P-PDOT. 30 This finding considerably complexified the field of GPCR, as we attempted to comment.…”

Section: Functionality and Biaismmentioning

confidence: 99%

“…Furthermore, we also launched the validation and assessment of the β‐arrestin recruitment, 55 a test reported to indicate the desensitization of the receptor, 56 or the less explored use of impedance measurement 57 . It turned recently out that the biased approach blurred the picture of agonist/antagonist 58–60 . Indeed, once examined with a multitude of functional assays each addressing a different pathway, agonists at this pathway could be neutral at another one or, even worse, antagonist at a third one, as in the case, for example, of the classical reference antagonists at melatonin receptors, luzindole and 4‐P‐PDOT 30 .…”

Section: From Melatonin Receptor To Drug Candidate An Industrial Appr...mentioning

confidence: 99%

Industrial and academic approaches to the search for alternative melatonin receptor ligands: An historical survey

Bedini,

Boutin,

Legros

et al. 2024

Journal of Pineal Research

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The search for melatonin receptor agonists formed the main part of melatonin medicinal chemistry programs for the last three decades. In this short review, we summarize the two main aspects of these programs: the development of all the necessary tools to characterize the newly synthesized ligands at the two melatonin receptors MT1 and MT2, and the medicinal chemist's approaches to find chemically diverse ligands at these receptors. Both strategies are described. It turns out that the main source of tools were industrial laboratories, while the medicinal chemistry was mainly carried out in academia. Such complete accounts are interesting, as they delineate the spirits in which the teams were working demonstrating their strength and innovative character. Most of the programs were focused on nonselective agonists and few of them reached the market. In contrast, discovery of MT1‐selective agonists and melatonergic antagonists with proven in vivo activity and MT1 or MT2‐selectivity is still in its infancy, despite the considerable interest that subtype selective compounds may bring in the domain, as the physiological respective roles of the two subtypes of melatonin receptors, is still poorly understood. Poly‐pharmacology applications and multitarget ligands have also been considered.

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Emergent Concepts of Receptor Pharmacology

Cited by 12 publications

References 111 publications

A Molecular Landscape of Mouse Hippocampal Neuromodulation

A Molecular Landscape of Mouse Hippocampal Neuromodulation

A simple mechanistic terminology of psychoactive drugs: a proposal

Industrial and academic approaches to the search for alternative melatonin receptor ligands: An historical survey

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