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 a...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 1995-09, Vol.38 (18), p.3593-3601
Main Authors: Oberlender, Robert, Ramachandran, P. V, Johnson, Michael P, Huang, Xuemei, Nichols, David E
Format: Article
Language:English
Subjects:
Amphetamines - chemistry
Amphetamines - metabolism
Amphetamines - pharmacology
Animals
Biological and medical sciences
Hallucinogens - chemistry
Hallucinogens - metabolism
Hallucinogens - pharmacology
Lysergic Acid Diethylamide - pharmacology
Male
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Rats
Rats, Sprague-Dawley
Receptors, Serotonin - metabolism
Serotoninergic system
Stereoisomerism
Structure-Activity Relationship
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00018a019