Effect of a chiral 4-alkyl substituent in hallucinogenic amphetamines

The potency of hallucinogenic amphetamine derivatives of the 1-(2,5-dimethoxy-4-alkylphenyl)-2-aminopropane type drops dramatically when the length of the 4-alkyl substituent exceeds propyl or when the substituent is branched. This investigation was directed toward evaluating changes in behavioral and biochemical pharmacology resulting from introducing chirality into the 4-alkyl group of such analogues. Two diastereoisomeric derivatives of this class containing a 4-(R or S)-2-butyl substituent, 11a,b, respectively, were studied. A slight but nonsignificant potency difference in d-lysergic acid diethylamide tartrate (LSD)-like discriminative stimulus properties and equal affinity for [125I]-(R)-(2,5-dimethoxy-4-iodophenyl) isopropylamine-labeled serotonin 5-HT2A/C radioligand-binding sites were observed. Thus, the portion of the receptor that interacts with the 4-alkyl substituent on hallucinogenic amphetamines does not present a highly asymmetric environment to the ligand. However, since both test drugs had higher binding affinity but lower LSD-like behavioral potency than the prototype compound with a 4-methyl group ((2,5-dimethoxy-4-methylphenyl)isopropylamine, 2), 11a,b may differ in their receptor agonist efficacy from more behaviorally active compounds such as 2.