Abstract

Forty-one compounds structurally related to diphenhydramine have been investigated for their antihistamine and atropine-like activities, central nervous system effect, and acute toxicity. They are of the following structures: (A) dimethylaminoethylbenzhydryl ethers with substitutions on the ring, (B) aminoethylbenzhydryl ethers with substitutions at the amino group and on the ring, (C) dimethylaminoethylhenzhydryl ethers with the phenyl radical replaced by an aryl radical. It was found that para-substitution of one phenyl ring with a halogen, a methyl or an ethyl group enhances the antihistaminic potency but reduces atropine-like activity. Substitution at the ortho-or at the meta-positions by these groups, on the other hand, results in a decrease in antihistaminic potency. The atropine-like activity is not significantly affected by such substitution. With the exception of the meta-chloro-analogue which is more toxic than the parent compound, no marked difference is evident in acute toxicity between these compounds and diphenhydramine (on weight basis). The addition of another group to the same or to the other phenyl radical at any position causes a diminution in both antihistaminic and atropine-like activities.

The piperidino and the pyrrolidino radical are as effective as the dimethylamino group in imparting an antihistaminic and an atropine-like property to the benzhydrylethyl ether molecule. The morpholino and certain other alkyl groups are less effective. In these compounds the substitution of another group in the phenyl ring has qualitatively the same effect upon the antihistaminic and atropine-like activities as does the same substitution in diphenhydramine.

When one phenyl radical in diphenhydramine is replaced by a thienyl, a naphthyl, or a cyclohexyl radical, the antihistaminic activity is decreased or abolished, but the atropine-like activity is not affected.