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Séminaire Chimie ED459

Multi-target and functionally selective approaches for potential treatments of psychiatric and neurodegenerative disorders

Dr. Paweł Zajdel (Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland)

publié le

Le Jeudi 05 octobre 2017 à 14h
ENSCM amphithéâtre Godechot (campus Balard, 240 av. Émile-Jeanbrau)

G protein coupled receptors (GPCR), known as seven transmembrane helical receptors, are a major source of new pharmaceutical. They are still a focus of intense research in academic and pharma laboratories. The current advances in pharmacology of GPCR became an incentive for medicinal chemists to search for small molecules that display selective polypharmacology and/or biased activity. Such compounds, with ability to modulate (agonists/antagonists) the selected biological targets or derivatives with greater preference to effector proteins and their subsequent signaling cascades, could provide drugs which enhance positive effects through favoring one path or producing reduced side-effects.

A multi-target approach remains the mainstream in the development of schizophrenia pharmacotherapy. The existing unmet medical needs for the control of psychoses, differences in expectable adverse events, and patient tolerance encourage the challenging initiatives to develop new antipsychotics. Herein, a strategy behind more efficacious therapies for the relief of the “negative” and cognitive symptoms of schizophrenia will be presented. Compounds with a multi-receptor profile were designed through the combination of privileged structures present in selected antipsychotics and compounds evaluated in preclinical and clinical trials.[1] An approach allowed identification of a lead compound, which showed partial 5-HT1A agonism, 5-HT2A, D2, and marked 5-HT7 antagonism, as a potential atypical antipsychotic to address the “positive”-like symptoms, reverse the “negative”-like symptoms, and reverse cognitive deficits associated with schizophrenia, without producing catalepsy.

For presentation of the second approach, the serotonin 5-HT6 receptor and its modulators were chosen. This receptor apart from canonical Gs-adenylyl cyclase pathway has complex and diverse signalling properties e.g., extracellular-regulated kinase (ERK)1/2, mammalian target of rapamycin (mTOR) and/or neurofibromin.[2] Extending efforts to develop functionally selective compounds, a scaffold-hoping approach and structure simplification allowed identification of novel classes of 5-HT6R antagonists /inverse agonists in cAMP signaling paths. Such strategy may provide potential medications in the treatment of disorders characterized by cognitive impairments e.g., schizophrenia, Alzheimer’s disease or cognitive disorders caused by genetic abnormalities.[3]

References

1. P. Zajdel, K. Marciniec, K. Kamiński, V. Canale, A.J. Bojarski, T. Kos, P. Popik, Azinesulfonamides of cyclic amine derivatives, manufacturing and use thereof. Patent WO/2016/003296.
2. K. Grychowska, G. Satała, K. Kos, P. Partyka, E. Colacino, S. Chaumont-Dubel, X. Bantreil, A. Wesołowska, M. Pawłowski, J. Martinez, P. Marin, G. Subra, A.J. Bojarski, F. Lamaty, P. Popik, P. Zajdel, Novel 1H-pyrrolo[3,2-c]quinoline based 5-HT6 receptor antagonists with potential application for the treatment of cognitive disorders associated with Alzheimer’s disease. ACS Chem. Neurosci. 2016, 7, 972.
3. D.W. Nadim, S. Chaumont-Dubel, F. Madouri, L. Cobret, M-L. de Tauzia, P. Zajdel, H. Benedetti, P. Marin, S. Morisset Lopez, A physical interaction between neurofibromin and serotonin 5HT6 receptor promotes receptor constitutive activity. Proc. Natl. Acad. Sci. USA 2016, 113, 12310.

Contact Local IBMM : Prof. Gilles Subra (DAPP)

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