Chemical synthesis and pharmacology of 6- and 7-hydroxylated 2-carbomethoxy-3-(p-tolyl)tropanes

Antagonism of cocaine's locomotor stimulant effects

L. Zhao, K. M. Johnson, M. Zhang, J. Flippen-Anderson, A. P. Kozikowski

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

In our efforts to identify molecules that might act as cocaine antagonists or cocaine partial agonists, efforts were made to further capitalize on our earlier finding regarding the ability of a 7-methoxylated pseudococaine analogue to act as a weak cocaine functional antagonist. Herein, a series of the 6- and 7-hydroxylated WIN analogues possessing a boat or chair conformation of the tropane ring were prepared and tested for their ability to displace [3H]mazindol binding and to inhibit high-affinity monoamine uptake into rat brain nerve endings. These 6- and 7-hydroxylated WIN analogues were readily prepared by use of a classical Willstatter synthesis to construct an appropriately functionalized tropane ring followed by use of a Suzuki coupling reaction to introduce the aryl group at position 3. Reduction of the resulting tropene by use of SmI2 or by catalytic hydrogenation followed by deprotection delivered the final target compounds. Some of these compounds were found to retain considerable affinity as inhibitors of the dopamine transporter (DAT) and the norepinephrine transporter (NET), but they were less potent inhibitors of the serotonin transporter (SERT). None of the compounds of the present series revealed any substantial potency difference in [3H]mazindol binding versus [3H]DA uptake, and failed to show 'cocaine antagonism' when tested for their ability to prevent cocaine's inhibition of DA transport. However, one of these hydroxylated WIN analogues, namely 12b, which possesses nanomolar potency at the DAT and NET and micromolar potency at the SERT, when tested in vivo, was found capable of attenuating cocaine's locomotor activity (AD50 = 94 mg/kg). Taken together, this work provides further support for our hypothesis that drugs that lack the ability to inhibit transport by all three monoaminergic transporters may exhibit 'partial' cocaine-like properties, but act as cocaine antagonists. Consequently, it may prove valuable to examine the behavioral activity of other 6- and 7-substituted tropanes in animal behavioral paradigms in the search for a cocaine medication.

Original languageEnglish (US)
Pages (from-to)3283-3294
Number of pages12
JournalJournal of Medicinal Chemistry
Volume43
Issue number17
DOIs
StatePublished - Aug 24 2000

Fingerprint

Tropanes
Cocaine
Pharmacology
Mazindol
Norepinephrine Plasma Membrane Transport Proteins
Serotonin Plasma Membrane Transport Proteins
Dopamine Plasma Membrane Transport Proteins
Hydrogenation
Nerve Endings
Ships
Boats
Locomotion
Conformations
Rats
Brain
Animals

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Chemical synthesis and pharmacology of 6- and 7-hydroxylated 2-carbomethoxy-3-(p-tolyl)tropanes : Antagonism of cocaine's locomotor stimulant effects. / Zhao, L.; Johnson, K. M.; Zhang, M.; Flippen-Anderson, J.; Kozikowski, A. P.

In: Journal of Medicinal Chemistry, Vol. 43, No. 17, 24.08.2000, p. 3283-3294.

Research output: Contribution to journalArticle

Zhao, L. ; Johnson, K. M. ; Zhang, M. ; Flippen-Anderson, J. ; Kozikowski, A. P. / Chemical synthesis and pharmacology of 6- and 7-hydroxylated 2-carbomethoxy-3-(p-tolyl)tropanes : Antagonism of cocaine's locomotor stimulant effects. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 17. pp. 3283-3294.
@article{539b5768dd0142c0bf3e4307098cf9b3,
title = "Chemical synthesis and pharmacology of 6- and 7-hydroxylated 2-carbomethoxy-3-(p-tolyl)tropanes: Antagonism of cocaine's locomotor stimulant effects",
abstract = "In our efforts to identify molecules that might act as cocaine antagonists or cocaine partial agonists, efforts were made to further capitalize on our earlier finding regarding the ability of a 7-methoxylated pseudococaine analogue to act as a weak cocaine functional antagonist. Herein, a series of the 6- and 7-hydroxylated WIN analogues possessing a boat or chair conformation of the tropane ring were prepared and tested for their ability to displace [3H]mazindol binding and to inhibit high-affinity monoamine uptake into rat brain nerve endings. These 6- and 7-hydroxylated WIN analogues were readily prepared by use of a classical Willstatter synthesis to construct an appropriately functionalized tropane ring followed by use of a Suzuki coupling reaction to introduce the aryl group at position 3. Reduction of the resulting tropene by use of SmI2 or by catalytic hydrogenation followed by deprotection delivered the final target compounds. Some of these compounds were found to retain considerable affinity as inhibitors of the dopamine transporter (DAT) and the norepinephrine transporter (NET), but they were less potent inhibitors of the serotonin transporter (SERT). None of the compounds of the present series revealed any substantial potency difference in [3H]mazindol binding versus [3H]DA uptake, and failed to show 'cocaine antagonism' when tested for their ability to prevent cocaine's inhibition of DA transport. However, one of these hydroxylated WIN analogues, namely 12b, which possesses nanomolar potency at the DAT and NET and micromolar potency at the SERT, when tested in vivo, was found capable of attenuating cocaine's locomotor activity (AD50 = 94 mg/kg). Taken together, this work provides further support for our hypothesis that drugs that lack the ability to inhibit transport by all three monoaminergic transporters may exhibit 'partial' cocaine-like properties, but act as cocaine antagonists. Consequently, it may prove valuable to examine the behavioral activity of other 6- and 7-substituted tropanes in animal behavioral paradigms in the search for a cocaine medication.",
author = "L. Zhao and Johnson, {K. M.} and M. Zhang and J. Flippen-Anderson and Kozikowski, {A. P.}",
year = "2000",
month = "8",
day = "24",
doi = "10.1021/jm000141b",
language = "English (US)",
volume = "43",
pages = "3283--3294",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "17",

}

TY - JOUR

T1 - Chemical synthesis and pharmacology of 6- and 7-hydroxylated 2-carbomethoxy-3-(p-tolyl)tropanes

T2 - Antagonism of cocaine's locomotor stimulant effects

AU - Zhao, L.

AU - Johnson, K. M.

AU - Zhang, M.

AU - Flippen-Anderson, J.

AU - Kozikowski, A. P.

PY - 2000/8/24

Y1 - 2000/8/24

N2 - In our efforts to identify molecules that might act as cocaine antagonists or cocaine partial agonists, efforts were made to further capitalize on our earlier finding regarding the ability of a 7-methoxylated pseudococaine analogue to act as a weak cocaine functional antagonist. Herein, a series of the 6- and 7-hydroxylated WIN analogues possessing a boat or chair conformation of the tropane ring were prepared and tested for their ability to displace [3H]mazindol binding and to inhibit high-affinity monoamine uptake into rat brain nerve endings. These 6- and 7-hydroxylated WIN analogues were readily prepared by use of a classical Willstatter synthesis to construct an appropriately functionalized tropane ring followed by use of a Suzuki coupling reaction to introduce the aryl group at position 3. Reduction of the resulting tropene by use of SmI2 or by catalytic hydrogenation followed by deprotection delivered the final target compounds. Some of these compounds were found to retain considerable affinity as inhibitors of the dopamine transporter (DAT) and the norepinephrine transporter (NET), but they were less potent inhibitors of the serotonin transporter (SERT). None of the compounds of the present series revealed any substantial potency difference in [3H]mazindol binding versus [3H]DA uptake, and failed to show 'cocaine antagonism' when tested for their ability to prevent cocaine's inhibition of DA transport. However, one of these hydroxylated WIN analogues, namely 12b, which possesses nanomolar potency at the DAT and NET and micromolar potency at the SERT, when tested in vivo, was found capable of attenuating cocaine's locomotor activity (AD50 = 94 mg/kg). Taken together, this work provides further support for our hypothesis that drugs that lack the ability to inhibit transport by all three monoaminergic transporters may exhibit 'partial' cocaine-like properties, but act as cocaine antagonists. Consequently, it may prove valuable to examine the behavioral activity of other 6- and 7-substituted tropanes in animal behavioral paradigms in the search for a cocaine medication.

AB - In our efforts to identify molecules that might act as cocaine antagonists or cocaine partial agonists, efforts were made to further capitalize on our earlier finding regarding the ability of a 7-methoxylated pseudococaine analogue to act as a weak cocaine functional antagonist. Herein, a series of the 6- and 7-hydroxylated WIN analogues possessing a boat or chair conformation of the tropane ring were prepared and tested for their ability to displace [3H]mazindol binding and to inhibit high-affinity monoamine uptake into rat brain nerve endings. These 6- and 7-hydroxylated WIN analogues were readily prepared by use of a classical Willstatter synthesis to construct an appropriately functionalized tropane ring followed by use of a Suzuki coupling reaction to introduce the aryl group at position 3. Reduction of the resulting tropene by use of SmI2 or by catalytic hydrogenation followed by deprotection delivered the final target compounds. Some of these compounds were found to retain considerable affinity as inhibitors of the dopamine transporter (DAT) and the norepinephrine transporter (NET), but they were less potent inhibitors of the serotonin transporter (SERT). None of the compounds of the present series revealed any substantial potency difference in [3H]mazindol binding versus [3H]DA uptake, and failed to show 'cocaine antagonism' when tested for their ability to prevent cocaine's inhibition of DA transport. However, one of these hydroxylated WIN analogues, namely 12b, which possesses nanomolar potency at the DAT and NET and micromolar potency at the SERT, when tested in vivo, was found capable of attenuating cocaine's locomotor activity (AD50 = 94 mg/kg). Taken together, this work provides further support for our hypothesis that drugs that lack the ability to inhibit transport by all three monoaminergic transporters may exhibit 'partial' cocaine-like properties, but act as cocaine antagonists. Consequently, it may prove valuable to examine the behavioral activity of other 6- and 7-substituted tropanes in animal behavioral paradigms in the search for a cocaine medication.

UR - http://www.scopus.com/inward/record.url?scp=0034710706&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034710706&partnerID=8YFLogxK

U2 - 10.1021/jm000141b

DO - 10.1021/jm000141b

M3 - Article

VL - 43

SP - 3283

EP - 3294

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 17

ER -