Abstract
A series of N-substituted 3α-[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-3α- (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-3α-[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 (K(i) 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)-3α-[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.
| Original language | English |
|---|---|
| Pages (from-to) | 4329-4339 |
| Number of pages | 11 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 40 |
| Issue number | 26 |
| DOIs | |
| State | Published - Dec 1 1997 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Organic Chemistry
Cite this
Novel N-substituted 3α-[bis(4'-fluorophenyl)methoxy]tropane analogues : Selective ligands for the dopamine transporter. / Agoston, Gregory E.; Wu, Jae H.; Izenwasser, Sari E; George, Clifford; Katz, Jonathan; Kline, Richard H.; Newman, Amy Hauck.
In: Journal of Medicinal Chemistry, Vol. 40, No. 26, 01.12.1997, p. 4329-4339.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Novel N-substituted 3α-[bis(4'-fluorophenyl)methoxy]tropane analogues
T2 - Selective ligands for the dopamine transporter
AU - Agoston, Gregory E.
AU - Wu, Jae H.
AU - Izenwasser, Sari E
AU - George, Clifford
AU - Katz, Jonathan
AU - Kline, Richard H.
AU - Newman, Amy Hauck
PY - 1997/12/1
Y1 - 1997/12/1
N2 - A series of N-substituted 3α-[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-3α- (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-3α-[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 (K(i) 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)-3α-[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.
AB - A series of N-substituted 3α-[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-3α- (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-3α-[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 (K(i) 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)-3α-[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.
UR - http://www.scopus.com/inward/record.url?scp=0031434059&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0031434059&partnerID=8YFLogxK
U2 - 10.1021/jm970525a
DO - 10.1021/jm970525a
M3 - Article
C2 - 9435902
AN - SCOPUS:0031434059
VL - 40
SP - 4329
EP - 4339
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 26
ER -