1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene (H2-PAT): Effect of stereochemistry on binding and function at brain histamine receptors

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Medicinal Chemistry Research


We report the synthesis, separation, receptor binding, and functional effects on mammalian brain dopamine synthesis of the isomers of 1-phenyl-3- dimethylamino-1,2,3,4-tetrahydronaphthalene (1-phenyl-3-aminotetralin, H2- PAT). The trans-(1R,3S)-(-)-H2-PAT isomer has highest affinity (K0.5 ~ 0.3 and 1.4 nM, respectively) and the cis-(1R,3R)-(+) isomer has lowest affinity (K0.5 ~ 70 and 340 nM, respectively) at histamine H1-type receptors labeled by [3H]-trans(-)-H2-PAT and [3H]-mepyramine in guinea pig brain. In general, our results suggest that stereochemistry at C1 and especially C3 is critically important for affinity of PAT and other diarylaminopropane-containing molecules at histamine H1-type receptors. At 1.0 μM, the two H2-PAT diastereomeric pairs and the racemates stimulate dopamine synthesis by activation of tyrosine hydroxylase to a similar extent (ca. 120% of control). These results are discussed in light of recent findings that [3H]-trans(-)-H2-PAT may radiolabel a presynaptic subpopulation of histamine H1-type receptors in mammalian forebrain.

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