Abstract
A‐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 (pK~1~ = 8.79) for cerebral cortex‐derived α‐2 adrenoceptors assayed with [^3^H] rauwolscine. The R‐enantiomer showed a tenfold greater affinity (pk~1~ = 9.09) for these receptors than the S‐enantiomer (pK~1~ = 8.10). A‐75169 HCI and both enantiomers had potent antagonistic effects at postsynaptic α‐2 adrenoceptors (pA~2~ values 7.31–7.49, dog saphenous vein). The racemate and the R‐enantiomer were moderately potent as antagonists for presynaptic α‐2 adrenoceptors (pA~2~ values 7.06 and 7.09, respectively, rat vas deferens), and they were more potent inhibitors (ID~50~ = 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 (pIC~50~ = 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 a potentially novel antiglaucoma compound. © 1993 Wiley‐Liss, Inc.