Hunger and associates(1) reported on the synthesis of a series of 1-(2-dialkylaminoethyl) -2-benzyl-5-nitro-benzimidazoles. These compounds were subsequently described as a new class of potent analgetics (2). Following these reports, several others appeared describing the synthesis and analgetic activity of a number of analogs in which various substitutions on the 2-benzyl benzimidazole nucleus were made. The structure-activity relationships of these compounds were reviewed by Beckett and Casy(3). The purpose of this study was to explore the structure-activity relationships of some 1-(2-dialkylaminoethyl) -2-phenoxymethyl benzimidazoles produced by varying substitutions on the benzimidazole and phenyl rings. In addition, the effects of alteration of the alkyl groups on the nitrogen of the ethyl amino side chain of certain derivatives were compared.Methods. Analgetic activity as well as acute toxicity was determined in male, Swiss-Webster mice using a modification of the hot plate method of Woolfe and MacDonald( 4 ) . The heat source was a 250 watt infrared lamp (General Electric) to which 18 volts were applied from a variable transformer. One mouse at a time was placed on the surface of the bulb and the time recorded until the animal jumped off. The sum of 4 consecutive trials was recorded as the reaction time. Reaction times were recorded 3 times for each mouse approximately 20 minutes apart before a drug was administered. Any animal showing a reaction time greater than 6 seconds on the third trial was discarded. The reaction times of the animals were then determined a t 30, 60 and 90 minutes following subcutaneous administration of drugs. A 60 second cut off time was utilized for mice which did not jump off the bulb. Since no significant difference could be demonstrated between reaction times determined 30 and 60 minutes following administration of any of the drugs tested, it was decided to use a function of the 30 minute post drug reaction time as the response metameter. Since animals which displayed reaction times greater than 6 seconds on the third trial before drug administration were discarded, the number of animals in dose groups were frequently unequal, ranging from 6 to 10 animals per group. For this reason the unsymmetrical bioassay described by Finney (5) was used to compare statistically the analgetic activity of the analogs to a doseresponse regression derived from responses to 2, 4 and 8 mg/kg of morphine sulfate. This statistical method provides for the assessment of potency relative to a standard. A value of 100 has been assigned to the potency of morphine sulfate in this bioassay, hence the relative potency (R) calculated for each analog is in terms of % of morphine sulfate activity .Acute toxicity, as reflected by lethality within 24 hours following injection of drugs was conducted in Swiss-Webster mice. Intraperitoneal LD-50 values were obtained by determining the effect of 3 dose levels yielding between 10 and 90% effect. At least 10 mice were utilized in determining each point. The computati...

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