Corneal application of enalkiren (ABBOTT-64662), [N-(3-amino-3-methyl-1- oxobutyl)-4-methoxy-L-phenylalanyl]-N-[1S,2R,3S)-1-(cyclohexylmethyl+ ++)-2,3- dihydroxy-5-methylhexyl]-L-histidinamide], a renin inhibitor compound, lowered intraocular pressure (IOP) in unanesthetized rabbits and anesthetized monkeys. IOP was significantly decreased for at least 60 minutes after administration of a 0.3% solution of enalkiren in monkeys and for at least 90 minutes after the administration of 0.1% and 0.3% solutions in rabbits. Enalkiren did not affect systemic blood pressure or heart rate in anesthetized monkeys after topical application to the cornea. The IOP lowering activity of enalkiren suggests a potential functional role for the renin angiotensin system in the modulation of IOP.

Captopril, an angiotensin II converting enzyme (ACE) inhibitor, was evaluated for potential antidepressive activity on the forced swim-induced behavioral despair (immobility) test in mice. Captopril (10.0 and 30.0, mg/kg ip) significantly reduced immobility and mimicked the effects of the antidepressants imipramine (30.0 mg/kg, ip) and mianserin (3.0, 10.0, and 30.0 mg/kg, ip). Captopril increased the motor activity of mice at these same dosages. Naloxone (2.0 mg/kg, ip) blocked the effects of captopril (30.0 mg/kg, ip) in the swim test. These data suggest that captopril has potential antidepressive activity. However, the conclusion is guarded, as the positive effects may be related to motor stimulation. The blockade of the captopril effects by naloxone suggests that brain opioid peptides play a role in this behavioral effect of captopril.

Seven N-substituted 1,2,3,4-tetrahydro-1- and three 2-naphthylamines were prepared and tested for local anesthetic activity in the rabbit corneal reflex test and the mouse sciatic nerve block test. At 0.1 and 1%, three 1-alkylamino compounds had durations of action comparable to that of tetracaine in the rabbit corneal reflex test and were considerably more potent than lidocaine. The other four 1-alkylamino derivatives were inactive or at best minimally active. The durations of action of 1% concentrations of the three 2-alkylamino compounds were equivalent to that of 1% lidocaine in the corneal reflex test. In the mouse sciatic nerve block test, the three active 1-alkylamino compounds were considerably longer acting than either tetracaine or lidocaine. Three1-alkylamino and the three 2-alkylamino compounds showed toxicity equal to or greater than lidocaine, while two 1-alkylamino and two 2-alkylamino compounds showed toxicity equal to or greater than tetracaine by the intraperitoneal route in mice. N-Heptyl-1,2,3,4-tetrahydro-6-methoxy-1-naphthylamine methanesulfonate was the most promising local anesthetic in these series.

N-Heptyl-1,2,3,4-tetrahydro-6-met,hoxy-1-naphthylamine methanesulfonate (I) is a potent, long lasting local anesthetic. It was as potent as tetracaine and at least 10 times more potent than lidocaine in the rabbit corneal reflex, guinea pig wheal, and mouse sciatic nerve block tests. The threshold anesthetic concentration (TAC), defined as the concentration required to produce anesthesia lasting 5 min, was calculated from each linear regression line fitted to the log dose-duration data, and these values were used to compare the potencies of the local anesthetics. In the rabbit corneal reflex test, the TAC values were 0.04% for I. 0.04% for tetracaine, and 0.66% for lidocaine. In the guinea pig wheal test, I had a TAC of 0.02%, which was equipotent to tetracaine and 11 times more potent than lidocaine; epinephrine (1:100,000) prolonged the duration of action of all three local anesthetics but had the least effect with I. In the mouse sciatic nerve block test, the TAC values were 0.06% for I, 0.10% for tetracaine, and 0.86% for lidocaine. The acute LDm values of I in mice were 138 mg/kg sc and 26 mg/kg iv. By either route, I was less toxic than tetracaine and more toxic than lidocaine. Comparison of the LD50 and TAC values in the mouse sciatic nerve block test indicated that I had a greater therapeutic index than either reference standard.

Acute oral toxicity studies were carried out with 16 solvents in newborn rats, in 14-day olds, in young adult and in older adult rats to find the approximate doses inducing the first observable signs of toxic action. These doses were divided by 1000 or 10,000 to arbitrarily select “permissible” solvent residue limits. Eight of the solvents tested (acetone, acetonitrile, benzene, chloroform, cyclohexane, diethyl ether, dimethyl formamide, ethyl alcohol, hexane, isopropyl alcohol, isopropyl ether, methyl alcohol, methylene chloride, methyl ethyl ketone, tetrahydrofuran, and toluene) were significantly more toxic in 14-day-old rats than in young adult rats. Cyclohexane and methyl alcohol were significantly more toxic in older adult than in young adult rats. Newborn rats were uniformly and exceedingly sensitive to these solvents. Special evaluation was given to ethyl alcohol, methyl alcohol, benzene, and chloroform because of currently available documentation for these solvents with respect to their potential for toxicity.

A relatively large dose of ABBOTT-16612 was tolerated by most species when the compound was given as a single oral dose to mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, swine, rhesus monkeys, African green monkeys, chimpanzees, and quail.