Chemistry and biology of the 2β-alkyl-3β-phenyl analogues of cocaine : subnanomolar affinity ligands that suggest a new pharmacophore model at the C-2 position

A series of 2 beta-alkyl-3 beta-phenyltropanes (i.e., the 2 beta-alkyl analogues of the WIN series) were prepared as analogues of cocaine and tested for their ability to displace [3H]mazindol binding and to inhibit high-affinity dopamine uptake into striatal nerve endings (synaptosomes). These 2 bet...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1995-08, Vol.38 (16), p.3086-3093
Main Authors: KOZILOWSKI, A. P, EDDINE SAIAH, M. K, JOHNSON, K. M, BERGMANN, J. S
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Carrier Proteins - metabolism
Cocaine - analogs & derivatives
Cocaine - metabolism
Corpus Striatum - metabolism
Dopamine - metabolism
Dopamine Plasma Membrane Transport Proteins
Ligands
Mazindol - metabolism
Medical sciences
Membrane Glycoproteins
Membrane Transport Proteins
Miscellaneous
Nerve Tissue Proteins
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Rats
Receptors, Drug - metabolism
Structure-Activity Relationship
Synaptosomes - metabolism
Tropanes - chemistry
Tropanes - metabolism
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Summary:A series of 2 beta-alkyl-3 beta-phenyltropanes (i.e., the 2 beta-alkyl analogues of the WIN series) were prepared as analogues of cocaine and tested for their ability to displace [3H]mazindol binding and to inhibit high-affinity dopamine uptake into striatal nerve endings (synaptosomes). These 2 beta-alkyl analogues were readily prepared in optically pure form starting from cocaine by proceeding through the 2 beta-phenyl-bearing aldehyde 6 as a key intermediate. Wittig reaction of 6 with the appropriate phosphorane and hydrogenation delivered the final products. All new compounds with the exception of 8e were found to exhibit nanomolar or subnanomolar affinity for the cocaine binding site in the rat striatum. These results are in apparent opposition to the binding model previously proposed which suggests a hydrogen bond donor-acceptor interaction to be present in the vicinity of the C-2 substituent. Taken together with our previous reports and recent findings from other laboratories, we suggest a new pharmacophore model in which 2 beta-substituents lacking H-bond acceptors enhance affinity to the binding site through hydrophobic interactions. The new SAR data contained herein may be relevant to the design of possible cocaine antagonists.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00016a012