Role of a conserved lysine residue in the peripheral cannabinoid receptor (CB2): evidence for subtype specificity. Mol Pharmacol

The human cannabinoid receptors, central cannabinoid recep-tor (CB1) and peripheral cannabinoid receptor (CB2), share only 44 % amino acid identity overall, yet most ligands do not dis-criminate between receptor subtypes. Site-directed mutagen-esis was employed as a means of mapping the ligand recog-nition site for the human CB2 cannabinoid receptor. A lysine residue in the third transmembrane domain of the CB2 receptor (K109), which is conserved between the CB1 and CB2 recep-tors, was mutated to alanine or arginine to determine the role of this charged amino acid in receptor function. The analogous mutation in the CB1 receptor (K192A) was found to be crucial for recognition of several cannabinoid compounds excluding (R)-(1)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyr-rolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)methanon