A series of 2-amino-1-(4-substituted-2,5-dimethoxyphenyl)butanes (Table V) was prepared as analogues of (R)-2-amino-1-(2,5-dimethoxy-4-methylphenyl)butane (1a). 1-(2,5-Dimethoxyphenyl)-2-(N-phthalimido)butane (7) was utilized as a synthetic intermediate common to many of the target compounds. Animal data are presented indicating that most of these analogues have low hallucinogenic potential. Selected compounds were compared with 1a in an avoidance-response acquisition model which differentiates between 1a and the human hallucinogens DOM (2a) and DOET (2b). Structure-activity relationships of these analogues are discussed.
The behavioral effects of R-2-amino-1-(2,5-dimethoxy-4-methylphenyl) butane or BL-3912A were compared with those of S-Amphetamine and R-DOM. BL-3912A facilitated acquisition of shuttle box responding by rats without increasing noncontingent intertrial (ITI) activity, while S-Amphetamine increased both avoidance and ITI responding. R-DOM had a biphasic effect on avoidance responding, increasing it at low doses and disrupting at higher doses. At doses that facilitated shuttle box responding, BL-3912A had no effect on unacclimated motor activity of rats nor on the rate of continuous avoidance responding by rats. S-Amphetamine increased the frequency of both motor activity and operant avoidance responding, while R-DOM decreased motor activity and increased operant avoidance responding. By facilitating avoidance behavior without increasing othermeasures of psychomotor activity, BL-3912A represents a unique psychopharmacological agent clearly different from R-DOM and S-Amphetamine.
A comparison of the behavioral pharmacology of DOM and amphetamine in rats indicated that lower doses (0.10-1.0 mg/kg) of the two agents had similar effects on schedule-controlled food-reinforced and shock-avoidance behavior. Similarities were also noted in their effects on horizontally directed motor activity when testing was preceeded by a period of acclimation. However, most doses of DOM tended to decrease unacclimated motor activity, while amphetamine increased this behavior. Neuropharmacological antagonism studies indicated that brain catecholamines (CA) and serotonin (5-HT) are involved in the behavioral effects of both DOM and amphetamine. Cinanserin, a 5-HT receptor blocker, attenuated the behavioral disruptive effects of both agents on food-reinforced responding. Cinanserin attenuated the effects of all doses of DOM and those of higher doses of amphetamine on shock avoidance. When given prior to lower doses of amphetamine, there was a greater behavioral stimulation than when amphetamine was given alone. Prior depletion of brain CA with alpha-methyltyrosine (alpha-MT) did not affect DOM induced disruption of food-reinforced responding, while alpha-MT attenuated the behavioral effects of all doses of DOM and amphetamine on shock avoidance. These data suggest that DOM and amphetamine share a similar component in their mechanism of action which depends on the availability of a releasable pool of brain CA.
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