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Novel N-substituted 3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues: selective ligands for the dopamine transporter.
J Med Chem. 1997 Dec 19; 40(26):4329-39.JM

Abstract

A series of N-substituted 3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues has been prepared that function as dopamine uptake inhibitors. The N-methylated analogue of this series had a significantly higher affinity for the dopamine transporter than the parent compound, N-methyl-3 alpha- (diphenylmethoxy)tropane (benztropine, Cogentin). Yet like the parent compound, it retained high affinity for muscarinic receptors. A series of N-substituted compounds were prepared from nor-3 alpha-[bis(4'-fluorophenyl)methoxy]tropane via acylation followed by hydride reduction of the amide or by direct alkylation. All compounds containing a basic tropane nitrogen displaced [3H]WIN 35,428 at the dopamine transporter (Ki range = 8.5-634 nM) and blocked dopamine uptake (IC50 range = 10-371 nM) in rat caudate putamen, whereas ligands with a nonbasic nitrogen were virtually inactive. None of the compounds demonstrated high binding affinity at norepinephrine or serotonin transporters. Importantly, a separation of binding affinities for the dopamine transporter versus muscarinic m1 receptors was achieved by substitution of the N-methyl group with other N-alkyl or arylalkyl substituents (eg. n-butyl, allyl, benzyl, 3-phenylpropyl, etc.). Additionally, the most potent and selective analogue in this series at the dopamine transporter, N-(4"-phenyl-n-butyl)-3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogue failed to substitute for cocaine in rats trained to discriminate cocaine from saline. Potentially, new leads toward the development of a pharmacotherapeutic for cocaine abuse and other disorders affecting the dopamine transporter may be discovered.

Authors+Show Affiliations

Psychobiology Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

9435902

Citation

Agoston, G E., et al. "Novel N-substituted 3 Alpha-[bis(4'-fluorophenyl)methoxy]tropane Analogues: Selective Ligands for the Dopamine Transporter." Journal of Medicinal Chemistry, vol. 40, no. 26, 1997, pp. 4329-39.
Agoston GE, Wu JH, Izenwasser S, et al. Novel N-substituted 3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues: selective ligands for the dopamine transporter. J Med Chem. 1997;40(26):4329-39.
Agoston, G. E., Wu, J. H., Izenwasser, S., George, C., Katz, J., Kline, R. H., & Newman, A. H. (1997). Novel N-substituted 3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues: selective ligands for the dopamine transporter. Journal of Medicinal Chemistry, 40(26), 4329-39.
Agoston GE, et al. Novel N-substituted 3 Alpha-[bis(4'-fluorophenyl)methoxy]tropane Analogues: Selective Ligands for the Dopamine Transporter. J Med Chem. 1997 Dec 19;40(26):4329-39. PubMed PMID: 9435902.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel N-substituted 3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues: selective ligands for the dopamine transporter. AU - Agoston,G E, AU - Wu,J H, AU - Izenwasser,S, AU - George,C, AU - Katz,J, AU - Kline,R H, AU - Newman,A H, PY - 1998/1/22/pubmed PY - 1998/1/22/medline PY - 1998/1/22/entrez SP - 4329 EP - 39 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 40 IS - 26 N2 - A series of N-substituted 3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues has been prepared that function as dopamine uptake inhibitors. The N-methylated analogue of this series had a significantly higher affinity for the dopamine transporter than the parent compound, N-methyl-3 alpha- (diphenylmethoxy)tropane (benztropine, Cogentin). Yet like the parent compound, it retained high affinity for muscarinic receptors. A series of N-substituted compounds were prepared from nor-3 alpha-[bis(4'-fluorophenyl)methoxy]tropane via acylation followed by hydride reduction of the amide or by direct alkylation. All compounds containing a basic tropane nitrogen displaced [3H]WIN 35,428 at the dopamine transporter (Ki range = 8.5-634 nM) and blocked dopamine uptake (IC50 range = 10-371 nM) in rat caudate putamen, whereas ligands with a nonbasic nitrogen were virtually inactive. None of the compounds demonstrated high binding affinity at norepinephrine or serotonin transporters. Importantly, a separation of binding affinities for the dopamine transporter versus muscarinic m1 receptors was achieved by substitution of the N-methyl group with other N-alkyl or arylalkyl substituents (eg. n-butyl, allyl, benzyl, 3-phenylpropyl, etc.). Additionally, the most potent and selective analogue in this series at the dopamine transporter, N-(4"-phenyl-n-butyl)-3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogue failed to substitute for cocaine in rats trained to discriminate cocaine from saline. Potentially, new leads toward the development of a pharmacotherapeutic for cocaine abuse and other disorders affecting the dopamine transporter may be discovered. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/9435902/Novel_N_substituted_3_alpha_[bis_4'_fluorophenyl_methoxy]tropane_analogues:_selective_ligands_for_the_dopamine_transporter_ L2 - https://dx.doi.org/10.1021/jm970525a DB - PRIME DP - Unbound Medicine ER -