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Alpha2-Adrenoceptors as targets for drug development

Description of Research

α2-Adrenoceptors of humans and other vertebrates are members of the G protein-coupled receptor superfamily and represent important drug targets. Three subtypes of these receptors are expressed in humans; the aim of this project is to identify approaches to selectively exploit subtype-selectivity in drug development. It is expected that this approach will help to identify agents with improved benefit-harm ratios.

α2A-Adrenoceptors mediate sedative and anaesthetic effects, regulate pain pathways, control the activity of the sympathetic nervous system, promote vasodilatation by stimulation of endothelial NO production, and inhibit insulin release from pancreatic β-cells. α2B-Adrenoceptors mediate vasoconstriction and promote proliferation of vascular smooth muscle cells. α2C-Adrenoceptors in the central nervous system are involved in regulation of neurotransmitter release and mediate complex modulatory effects on cognitive functions. The research employs methods ranging from molecular modelling and structural biology to clinical trials of novel pharmaceuticals. Gene-targeted mice have provided valuable model systems for the identification of subtype-specific receptor functions and applications.

Selected Publications

Lehto J, Johansson J, Vuorilehto L, Luoto P, Arponen E, Scheinin H, Rouru J, Scheinin M. Sensitivity of [11C]ORM-13070 to increased extracellular noradrenaline in the CNS - a PET study in human subjects. Psychopharmacology (Berl). 2015 Apr 29. [Epub ahead of print]

Lehto J, Hirvonen MM, Johansson J, Kemppainen J, Luoto P, Naukkarinen T, Oikonen V, Arponen E, Rouru J, Sallinen J, Scheinin H, Vuorilehto L, Finnema SJ, Halldin C, Rinne JO, Scheinin M. Validation of [11C]ORM-13070 as a PET tracer for α2C-adrenoceptors in the human brain. Synapse 2015; 69:172-81.

Posti JP, Salo P, Ruohonen S, Valve L, Muszkat M, Sofowora GG, Kurnik D, Stein CM, Perola M, Scheinin M, Snapir A. A polymorphism in the protein kinase C gene PRKCB is associated with α2-adrenoceptor-mediated vasoconstriction. Pharmacogenet Genomics 2013;23:127-34.

Ruohonen ST, Ruohonen S, Gilsbach R, Savontaus E, Scheinin M, Hein L. Involvement of α2-adrenoceptor subtypes A and C in glucose homeostasis and adrenaline-induced hyperglycaemia. Neuroendocrinology 2012;96:51-9.

Laurila JM, Wissel G, Xhaard H, Ruuskanen JO, Johnson MS, Scheinin M. Involvement of the first transmembrane segment of human α2-adrenoceptors in the subtype-selective binding of chlorpromazine, spiperone and spiroxatrine. Brit J Pharmacol 2011;164:1558-72.

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