Anales RANF

P.13 SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF 3’- DEOXY-(N)-METHANOCARBA-BASED ADENOSINE RECEPTOR LIGANDS M. Kock 1 , R. Liu 2 , L. H. Heitman 2 , K. A. Jacobson 3 , A. Junker 1 1 University of Muenster, Germany. 2 Leiden University, Netherlands. 3 National Institutes of Health, USA The bicyclo[3.1.0]hexane scaffold, often referred to as (N)-methanocarba, has been widely used as a ribose bioisostere in the development of nucleoside-derived A 3 adenosine receptor (A 3 AR) ligands. It is known to improve selectivity towards the other adenosine receptor subtypes (A 1 , A 2A , A 2B ) while maintaining high affinity. 1 While the 2’-OH-group of the corresponding adenosine derivatives is known to be important for A 3 AR affinity, 2 3’-deoxy-(N)-methanocarba adenosine derivatives were never synthesized and therefore never studied. The limited data for 3’-deoxyribose derivatives (e.g., compound 2 ) indicate affinities in a similar range to ribose-based compounds (see MRS1898 ( 1 )). 3,4 However, the reduced polar surface area of the new compound class promises more favorable physicochemical properties and thus improved pharmacokinetic behavior. Therefore 3’-deoxy-(N)- methanocarba adenosine derivatives are highly desirable compounds for studying SAR of A 3 AR ligands. Herein we report the first synthesis and pharmacological evaluation of 3’-deoxy-(N)- methanocarba-based adenosine receptor ligands. 1. Müller, C. E.; Jacobson, K. A. Biochem. Biophys. Acta 2011 , 1808 , 1290-1308. 2. Lee, K.; Ravi, G.; Ji, X.; Marquez, V. E.; Jacobson, K. A. Bioorg. Med. Chem. Lett. 2001 , 11 , 1333– 1337. 3. Tchilibon, S.; Joshi, B. V.; Kim, S.; Duong, H. T.; Gao, Z.; Jacobson, K. A. J. Med. Chem. 2005 , 48 , 1745-1758. 4. Siddiqi, S. M.; Olah, M. E.; Ji, X.; Melman, N.; Bellamkonda, K.; Meshulam, Y., Stiles, G. L.; Kim, H. O.; Jacobson, K. A. J. Med. Chem. 1995 , 38 , 1720-1735.