A-75169 HCL - PHARMACOLOGICAL PROFILE AND OCULAR PHARMACOLOGY STUDIES OF A NEW ALPHA-2 ANTAGONIST

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 alpha-2 receptor antagonism and amine uptake inhibition in a single molecule. A-75169 HCI showed high affinity (pK(I) = 8.79) for cerebral cortex-derived alpha-2 adrenoceptors assayed with [H-3] rauwolscine. The R-enantiomer showed a tenfold greater affinity (pK(I) = 9.09) for these receptors than the S-enantiomer (pK(I) = 8.10). A-75169 HCI and both enantiomers had potent antagonistic effects at postsynaptic alpha-2 adrenoceptors (pA2 values 7.31-7.49, dog saphenous vein). The racemate and the R-enantiomer were moderately potent as antagonists for presynaptic alpha-2 adrenoceptors (pA2 values 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 alpha-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 alpha-2 antagonist possessing amine uptake blocking properties, is a potentially novel antiglaucoma compound.