A series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs) previously was found to modulate tyrosine hydroxylase activity and dopamine synthesis in rodent forebrain through interaction with a binding site labeled by [³H]-(−)-(1R,3S)-trans-H₂-PAT. Recently, we have discovered that PATs also bind with high affinity to the [³H]mepyramine-labeled H₁ receptor in rat and guinea pig brain. Here, we report the synthesis and biological evaluation of additional PAT analogues in order to identify differences in binding at these two sites. Further molecular modifications involve the pendant phenyl ring as well as quaternary amine compounds. Comparison of about 38 PAT analogues, 10 structurally diverse H₁ ligands, and several other CNS-active compounds revealed no significant differences in affinity at [³H]-(−)-trans-H₂-PAT sites versus [³H]mepyramine-labeled H₁ receptors. These results, together with previous autoradiographic brain receptor-mapping studies that indicate similar distribution of [³H]-(−)-trans-H₂-PAT sites and [³H]mepyramine-labeled H₁ receptors, suggest that both radioligands label the same histamine H₁ receptors in rodent brain. We also report a revision of our previous comparative molecular field analysis (CoMFA) study of the PAT ligands that yields a highly predictive model for 66 compounds with a cross-validated R² (q²) value of 0.67. This model will be useful for the prediction of high-affinity ligands at radiolabeled H₁ receptors in mammalian brain.

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