THE PHARMACOLOGICAL ACTIVITY OF THE RING METHYL SUBSTITUTED PHENISOPROPYLAMINES

¹ Department of Pharmacology, West Virginia University School of Medicine Morgantown, West Virginia

1. 4-Methylphenisopropylamine, 3-methylphenisopropylamine, and 2-methylphenisopropylamine are only slightly less active than phenisopropylamine or amphetamine or about 1/200 to 1/250 as active as synthetic l-epinephrine as vasopressor agents in barbitalized and unanesthetized dogs, while 3,4-dimethylphenisopropylamine and 2,5-dimethylphenisopropylamine are only one-third to one-half as active.

2. All these compounds produce a decrease in tone in the isolated rabbit jejunum in concentrations of 1:4,000 with the 3,4-dimethyl isomer being most active. Similarly, they relax the guinea pig tracheal chain at a concentration of 1:4,000 and the 3,4-dimethyl isomer is slightly more active than the other agents and is almost 1/1,000 as active as epinephrine.

3. The 3-methyl, 4-methyl, and 3,4-dimethyl derivatives are about one-half as active as phenisopropylamine as analeptic agents in waking pentobarbitalized mice, while the 2-methyl and 2,5-dimethyl derivatives are almost inactive. In unanesthetized rats, the 3-methyl derivative is less than one-half as stimulant as phenisopropylamine, the 2-methyl about one-fourth, and the other compounds even less active. In unanesthetized mice, the 3,4-dimethyl and 3-methyl derivatives are most toxic and the 2-methyl and 2,5-dimethyl derivatives are least toxic.

4. The 4-methylphenisopropylamine produces anorexia in dogs although less on a weight basis than that produced by phenisopropylamine. The 3-methylphenisopropylamine has less activity and the other compounds are inactive.

5. Orally in man in doses of 1.0 mgm./kgm., the 4-methylphenisopropylamine produces very little change in blood pressure, some anorexia, and no obvious central nervous system stimulation, while the other methyl derivatives have very little effect at this dose. With 1.5 mgm./kgm. the anorexic effect of the 4-methyl compound becomes more apparent, is more prolonged, and is accompanied by sweating; the anorexic effect of the 3,4-dimethyl compound becomes apparent but is transient while the 2- and 3-methyl derivatives produce some slight central nervous system stimulation but little or no anorexia. With 2.0 mgm./kgm. the anorexic effect of the 4-methyl compound becomes severe and very prolonged, is accompanied by salivation, nausea, and vomiting; the 3,4-dimethyl compound is similar, while the 2- and 3-methyl derivatives do not have this effect. The 2,5-dimethylphenisopropylamine is almost inactive even at 2.0 mgm./kgm.

The effects of these ring methyl substituted phenisopropylamines on blood pressure and pulse rate are much less than the unsubstituted phenisopropylamine on a weight basis.