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Comparison of human, rat and mouse cannabinoid CB2 receptor primary sequences has shown significant divergence at the mRNA and protein sequence level, raising the possibility of species specific pharmacological properties. Additionally, given the importance of the dog as a non-rodent species for predicting human safety during the drug development process, we cloned the dog CB2 receptor gene and characterized its in-vitro pharmacological properties in a recombinant expression system. A 1.1 kb dog peripheral cannabinoid receptor (dCB2) fragment encoding a 360 amino acid protein was cloned from dog spleen cDNA. Analysis of the cloned dCB2 polypeptide sequence revealed that it shares between 76 and 82% homology with rat, mouse, human and predicted chimpanzee cannabinoid CB2 receptors. The dog CB2 receptor expressed in CHO cells displayed similar binding affinities for various synthetic and endogenous cannabinoids as compared to those measured for the human and rat cannabinoid CB2 receptors. However, these ligands exhibited altered functional potencies and efficacies for the dog cannabinoid CB2 receptor, which was also found to be negatively coupled to adenylate cyclase activity. These complex pharmacological differences observed across species for the cannabinoid CB2 receptor suggest that caution should be exerted when analyzing the outcome of animal efficacy and safety studies, notably those involving cannabinoid CB2 receptor targeting molecules tested in the dog.