Riefolo, F. | bioRxiv Science

bioRxiv2019

Novel Analgesic Agents Obtained by Molecular Hybridization of Orthosteric and Allosteric Ligands

Despite the high incidence of acute and chronic pain in the general population, the efficacy of currently available medications is unsatisfactory. Insufficient management of pain has a profound impact on the quality of life and can have serious physical, psychological, social, and economic consequences. This unmet need reflects a failure to develop novel classes of analgesic drugs with superior clinical properties and lower risk of abuse. Nevertheless, recent advances in our understanding of the neurobiology of pain are offering new opportunities for developing different therapeutic approaches. Among those, the activation of M2 muscarinic acetylcholine receptors, which play a key role in the cholinergic regulation of the nociceptive transmission, constitutes one of the most promising strategies. We have recently developed a small library of novel pharmacological agents by merging the structures of known orthosteric and allosteric muscarinic ligands through their molecular hybridization, an emerging approach in medicinal chemistry based on the combination of pharmacophoric moieties of different bioactive substances to produce a new compound with improved pharmacological properties. Herein we report the functional characterization of the new ligands in vitro and the assessment of their efficacy as analgesic agents and tolerability in mice. This work provides new insights for the development and optimization of novel muscarinic hybrid compounds for the management of pain.

pharmacology and toxicology↗

bioRxiv2019

Control of brain state transitions with light

Behavior is driven by specific neuronal activity and can be directly associated with characteristic brain states. The oscillatory activity of neurons contains information about the mental state of an individual, and the transition between physiological brain states is largely controlled by neuromodulators. Manipulating neural activity, brain rhythms or synchronization is of significant therapeutic interest in several neurological disorders and can be achieved by different means such as transcranial current and magnetic stimulation techniques, and by light through optogenetics, although the clinical translation of the latter is hampered by the need of gene therapy. Here, we directly modulate brain rhythms with light using a novel photoswitchable muscarinic agonist. Synchronous slow wave activity is transformed into a higher frequency pattern in the cerebral cortex both in slices in vitro and in anesthetized mice. These results open the way to the study of the neuromodulation and control of spatiotemporal patterns of activity and pharmacology of brain states, their transitions, and their links to cognition and behavior, in different organisms without requiring any genetic manipulation.

neuroscience↗