Are Caenorhabditis elegans receptors useful targets for drug discovery: Pharmacological comparison of tyramine receptors with high identity from C. elegans (TYRA-2) and Brugia malayi (Bm4)

The biogenic amine, tyramine (TA), modulates a number of key processes in nematodes and a number of TA-specific receptors have been identified. In the present study, we have identified a putative TA receptor (Bm4) in the recently completed Brugia malayi genome and compared its pharmacology to its putative Caenorhabditis elegans orthologue, TYRA-2, under identical expression and assay conditions. TYRA-2 and Bm4 are the most closely related C. elegans and B. malayi BA receptors and differ by only 14 aa in the TM regions directly involved in ligand binding. Membranes from HEK-293 cells stably expressing Bm4 exhibited specific, saturable, high affinity, [3H]LSD and [3H]TA binding with Kds of 18.1 ± 0.93 and 15.1 ± 0.2 nM, respectively. More importantly, both TYRA-2 and Bm4 TA exhibited similar rank orders of potencies for a number of potential tyraminergic ligands. However, some significant differences were noted. For example, chloropromazine exhibited an order of magnitude higher affinity for Bm4 than TYRA-2 (pKis of 7.6 ± 0.2 and 6.49 ± 0.1, respectively). In contrast, TYRA-2 had significantly higher affinity for phentolamine than Bm4. These results highlight the utility of the nearly completed B. malayi genome and the importance of using receptors from individual parasitic nematodes for drug discovery.