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

Alan P. Kozikowski, M. K. Eddine Saiah, Kenneth M. Johnson, John S. Bergmann

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

A series of 2β-alkyl-3β-phenyltropanes (i.e., the 2β-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 2β-alkyl analogues were readily prepared in optically pure form starting from cocaine by proceeding through the 2β-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 2β-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.

Original languageEnglish (US)
Pages (from-to)3086-3093
Number of pages8
JournalJournal of Medicinal Chemistry
Volume38
Issue number16
StatePublished - 1995

Fingerprint

Cocaine
Ligands
Phosphoranes
Bearings (structural)
Mazindol
Binding Sites
Corpus Striatum
Hydrogenation
Nerve Endings
Synaptosomes
Hydrophobic and Hydrophilic Interactions
Aldehydes
Rats
Hydrogen
Dopamine
Hydrogen bonds

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

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. / Kozikowski, Alan P.; Eddine Saiah, M. K.; Johnson, Kenneth M.; Bergmann, John S.

In: Journal of Medicinal Chemistry, Vol. 38, No. 16, 1995, p. 3086-3093.

Research output: Contribution to journalArticle

Kozikowski, Alan P. ; Eddine Saiah, M. K. ; Johnson, Kenneth M. ; Bergmann, John S. / 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. In: Journal of Medicinal Chemistry. 1995 ; Vol. 38, No. 16. pp. 3086-3093.
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