21.1. The endogenous cannabinoid system provides opportunities for drug development

Public examination of a doctoral dissertation in the field of pharmaceutical chemistry

Doctoral candidate: MSc (Med Chem), MSc (Pharm) Katri Raitio

Time and venue 21.1.2011 at 12 noon, Snellmania L22, Kuopio Campus

The endogenous cannabinoid system takes its name from the plant Cannabis sativa the therapeutic and psychotropic effects of which have been recognized for thousands of years. These effects are now known to be mediated via cannabinoid receptors. The main active ingredient of Cannabis sativa, Δ9-tetrahydrocannabinol, represented the starting point for synthetic cannabinoid development.

Since the discovery of the cannabinoid CB2 receptor, also referred to as “the peripheral cannabinoid receptor”, in 1993, the development of CB2 selective ligands has been attempted by research groups worldwide. Although most of the cannabinoid ligands developed prior to the discovery of CB2 receptor do exert their effects via that receptor, only a few of them possess adequate selectivity in terms of their effects at the CB1 receptor. Studies on the physiological role of CB2 and its malfunction and, on the other hand, changes in CB2 expression levels in certain medical conditions, have revealed numerous potential future indications for the use of CB2 receptor ligands.

In this study, a series of 2-oxoquinoline, quinoline, isoquinoline, naphthyl and coumarin derivatives were designed and synthesized in order to examine their CB2 activity and selectivity and thereby to discover novel potent and efficient CB2 receptor ligands for further drug development. The activities of the synthesized compounds were evaluated by measuring binding of the radioligand GTPgS to human CB2-transfected Chinese hamster ovary cell membranes and to rat cerebellar brain membranes expressing CB1 receptors.

One outcome of this study was the synthesis of several efficient and highly CB2-selective inverse agonists with nanomolar potencies. Structure-activity relationships were derived to outline the structural properties favourable to CB2 activity and selectivity which can benefit future studies. Novel CB2-selective agonist lead structures with micromolar potencies were also discovered and structure-activity relationships regarding CB2 agonist activity of this compound family were investigated. These structures provide promising starting points for further ligand development aiming at the development of potent, CB2- selective agonists, which may be of therapeutical value in the treatment of e.g. inflammatory diseases and pain.

The doctoral dissertation of Master of Science (Medicinal Chemistry), Master of Science (Pharmacy) Katri Raitio, entitled Design, Synthesis and In Vitro Evaluation of Novel Cannabinoid CB2 Receptor Ligands: A Structure-Activity Study will be examinedat the Faculty of Health Sciences. The opponent in the public examination will be Professor Mika Scheinin of the University of Turku, and the custos will be Professor Jouko Vepsäläinen of the University of Eastern Finland.

Contact: Katri Raitio, Yliopiston Apteekki, Tampere, katri.raitio@yliopistonapteekki.fi, tel. 050 527 3585

Publishing year: 2011

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