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.
Oberlender
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R
Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
Ramachandran
P V
PV
Johnson
M P
MP
Huang
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X
Nichols
D E
DE
D000662:Amphetamines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D006213:Hallucinogens / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000662:Amphetamines; D006213:Hallucinogens; D011985:Receptors, Serotonin; D008238:Lysergic Acid Diethylamide; C036157:2,5-dimethoxyamphetamine