AbstractA‐75169 HCI (1,2,3,4‐tetrahydro‐6‐hydroxy‐1‐[N‐methylamino)‐methyl‐N‐phenethyl]‐naphthalene HCI, a racemate, is derived from a series of compounds that combine selective α‐2 receptor antagonism and amine uptake inhibition in a single molecule. A‐75169 HCI showed high affinity (pK1= 8.79) for cerebral cortex‐derived α‐2 adrenoceptors assayed with [3H] rauwolscine. The R‐enantiomer showed a tenfold greater affinity (pk1= 9.09) for these receptors than the S‐enantiomer (pK1= 8.10). A‐75169 HCI and both enantiomers had potent antagonistic effects at postsynaptic α‐2 adrenoceptors (pA2values 7.31–7.49, dog saphenous vein). The racemate and the R‐enantiomer were moderately potent as antagonists for presynaptic α‐2 adrenoceptors (pA2values 7.06 and 7.09, respectively, rat vas deferens), and they were more potent inhibitors (ID50= 1.50 mg/kg, i.v., and 0.60 mg/kg, i.v., respectively) of clonidine‐induced mydriasis, an α‐2 mediated effect, than the S‐enantiomer. The S‐enantiomer was a more potent inhibitor of norepinephrine synaptosomal uptake than the R‐enantiomer (pIC50= 6.00 and 5.79, respectively). When applied topically to the eyes of rabbits (3.0% solution) and monkeys (0.3% solution), the racemate significantly reduced intraocular pressure (IOP). The topical administration of A‐75169 HCI (0.5% solution) to dog cornea did not affect blood pressure or heart rate. A‐75169 HCI, a selective α‐2 antagonist possessing amine uptake blocking properties, is