Department of Pharmaceutical Chemistry

Research group:
Tapio Nevalainen, Antti Poso, Susanna Saario, Teija Parkkari, Anna Minkkilä, Heikki Käsnänen, Raimo Saari, Minna Glad

Hemp plant Cannabis sativa is particularly known for its psychoactive drugs (cannabis, marijuana) and cannabinoids of which the D-9-tetrahydrocannabinol (THC) is the main psychoactive sustance. However cannabis has been used in medicine for thousands of years as an analgesic (relieves pain), an anti-emetic (relieves nausea and vomiting) and an appetite stimulant. Cannabinoids reduce intraocular pressure in glaucoma patients and helped with muscle spasms and stiffness in MS patients. The potential therapeutic benefits of cannabinoids is hampered by unwanted psychoactive effects of the cannabinoids.

Pharmacological research on cannabinoids during the last decades has led to the discovery of specific cannabinoid receptors (CB1, CB2) and an endocannabinoid signaling system and further development novel therapeutic agents based on this system. Recent findings indicate that the endocannabinoid system (Scheme) (hyperlink) plays a crucial role in human physiology. The proteins involved in the endocannabinoid system; CB1 and CB2 receptors, endocannabinoids: anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), endocannabinoid transport system, and hydrolysis enzymes (FAAH and MGL) that break down the endogenous ligands, are new potential targets for drug development.

Cannabinoid research has been a major target of interest at our group for over a decade. The effects of cannabinoids in the treatment of glaucoma (a disease characterized by increased intraocular pressure) have been studied as well as the application of prodrug technology for increasing the aqueous solubility of cannabinoid compounds in opthalmic formulations. The project has expanded into the area of discovering novel therapeutic agents based on cannabinoid receptors and endocannabinoid inactivation proteins by using modern ligand- and receptor-based drug design methods in 2000. Functional G-protein activation assays for CB1 and CB2 receptors and enzyme assay for FAAH and MGL activity have been developed in the project. Presently the main research interests of our group focus on development of specific FAAH and MGL inhibitors.

Research topics:

- Development of specific FAAH and MGL inhibitors
- Modeling of the cannabinoid receptors, FAAH and MGL-enzymes
- Development of CB2-ligands
- Development of the CB1-radioligand for PET imaging

Myllymäki MJ, Saario SM, Kataja AO, Castillo-Melendez JA, Nevalainen T, Juvonen RO, Järvinen T, Koskinen AMP, Design, Synthesis, and In Vitro Evaluation of Carbamate Derivatives of 2-Benzoxazolyl- and 2-Benzothiazolyl-(3-hydroxyphenyl)-methanones as Novel Fatty Acid Amide Hydrolase Inhibitors. J. Med. Chem. (ASAP) 2007.

Raitio KH, Savinainen JR, Nevalainen T, Järvinen T. Vepsalainen J. Synthesis and in vitro evaluation of novel 2-oxo-1,2-dihydroquinoline CB2 receptor inverse agonists. Chemical Biology & Drug Design 68, 334-340, 2006

Raitio KH, Savinainen JR, Vepsäläinen J, Laitinen JT, Poso A, Järvinen T, Nevalainen T. Synthesis and SAR Studies of 2-Oxoquinoline Derivatives as CB2 Receptor Inverse Agonists. J. Med. Chem. 49:2022-2027, 2006

Parkkari T, Salo OM, Huttunen KM, Savinainen JR, Laitinen JT, Poso A, Nevalainen T, Jarvinen T. Synthesis and CB1 receptor activities of dimethylheptyl derivatives of 2-arachidonoyl glycerol (2-AG) and 2-arachidonyl glyceryl ether (2-AGE). Bioorg. Med. Chem. 14, 2850-8, 2006

Saario SM, Poso A, Juvonen RO, Järvinen T, Salo-Ahen OMH: FAAH Inhibitors From Virtual Screening of the Endocannabinoid System. J. Med. Chem. 49: 4650-4656, 2006

Salo OMH, Savinainen JR, Parkkari T, Nevalainen T, Lahtela-Kakkonen M, Gynther J, Laitinen JT, Jarvinen T, Poso A: 3D-QSAR Studies on Cannabinoid CB1 Receptor Agonists: G-Protein Activation as Biological Data. J. Med. Chem. 49:554-566, 2006

Salo OMH, Raitio KH, Savinainen JR, Nevalainen T, Lahtela-Kakkonen M, Laitinen JT, Järvinen T, Poso A: Virtual screening of novel CB2 ligands using a comparative model of the human cannabinoid CB2 receptor. J. Med. Chem. 48: 7166-7171, 2005

Saario SM, Salo OMH, Nevalainen T, Poso A, Laitinen JT, Järvinen T, Niemi R: Characterization of the sulfhydryl-sensitive site in the enzyme responsible for hydrolysis of 2-arachidonoyl-glycerol in rat cerebellar membranes. Chem. Biol. 12:649-656, 2005

Salo OM, Lahtela-Kakkonen M, Gynther J, Järvinen T, Poso A. Development of a 3D model for the human cannabinoid CB1 receptor. J. Med. Chem. 47:3048-57, 2004

Saario SM, Savinainen JR, Laitinen JT, Järvinen T, Niemi R. Monoglyceride lipase-like enzymatic activity is responsible for hydrolysis of 2-arachidonoylglycerol in rat cerebellar membranes. Biochem. Pharmacol. 67:1381-7, 2004