Novel conformationally constrained tropane analogues by 6-endo-trig radical cyclization anti stille coupling - Switch of activity toward the serotonin anti/or norepinephrine transporter

Alexander Hoepping, Kenneth M. Johnson, Clifford George, Judith Flippen-Anderson, Alan P. Kozikowski

Research output: Contribution to journalArticle

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Abstract

A novel class of tricyclic tropane analogues has been synthesized by making use of radical cyclization technology in combination with the Stille coupling reaction. As hybrids between tropanes and quinuclidines, these tropaquinuclidines represent a significant structural departure from many of the other classes of tropane ligands synthesized to date. This structure class is characterized by the boat conformation of the tropane ring and the orientation of the additional bridge (and therefore of the nitrogen lone pair) together with the unusual placement of the aromatic moiety. All compounds were tested for their ability to inhibit monoamine reuptake under identical conditions. The ability to inhibit reuptake of dopamine in comparison to cocaine is generally decreased in this series but for one compound. (1S,3R,6S)-(Z)-9-(thienylmethylene)-7-azatricyclo[4.3.1.0]decane- 2β-carboxylic acid methyl ester (5h) exhibits reasonable activity at the dopamine transporter (DAT) (K(i) = 268 nM) and good activity at the norepinephrine transporter (NET) (K(i) = 26 nM). The potency and selectivity shown by some of these ligands for the NET, serotonine transporter (SERT), or NET/SERT is striking, particularly in view of the displacement of the aromatic ring in this series from its usual position at C-3 in the WIN analogues. Thus, (1S,3R,6S)-(Z)-9-(4-biphenylylmethylene)-7- azatricyclo[4.3.1.0]decane-2β-carboxylic acid methyl ester (5a) is a selective inhibitor of norepinephrine reuptake (K(i) = 12 nM). Its p-methoxy analogue 5c is a mixed inhibitor of norepinephrine and serotonin reuptake (K(i) = 187 nM at the NET and 56 nM at the SERT). The most active and selective compound we found in the present series is compound 8b [(1S,3R,6S)- 2-(acetoxymethyl)-(Z)9-(3,4-dichlorophenylmethylene)-7- azatricyclo[4.3.1.0]decane]. This compound is a potent (K(i) = 1.6 nM) and selective inhibitor of serotonin reuptake into rat midbrain synaptosomes. Its selectivity is about 400-fold over the NET and about 1000-fold over the DAT. The results of this study further demonstrate the possibility of tuning the selectivity of tropane analogues toward the SERT or NET binding site. The ligands disclosed herein provide additional pharmacological tools of use in attempting to correlate structure and transporter selectivity with in vivo studies of behavioral outcomes.

Original languageEnglish (US)
Pages (from-to)2064-2071
Number of pages8
JournalJournal of Medicinal Chemistry
Volume43
Issue number10
DOIs
StatePublished - 2000

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Tropanes
Norepinephrine Plasma Membrane Transport Proteins
Serotonin Plasma Membrane Transport Proteins
Cyclization
Serotonin
Switches
Dopamine Plasma Membrane Transport Proteins
Carboxylic Acids
Ligands
Esters
Quinuclidines
Ships
Synaptosomes
Serotonin Uptake Inhibitors
Boats
Mesencephalon
Cocaine
Crystal orientation
Conformations
Rats

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Novel conformationally constrained tropane analogues by 6-endo-trig radical cyclization anti stille coupling - Switch of activity toward the serotonin anti/or norepinephrine transporter. / Hoepping, Alexander; Johnson, Kenneth M.; George, Clifford; Flippen-Anderson, Judith; Kozikowski, Alan P.

In: Journal of Medicinal Chemistry, Vol. 43, No. 10, 2000, p. 2064-2071.

Research output: Contribution to journalArticle

Hoepping, Alexander ; Johnson, Kenneth M. ; George, Clifford ; Flippen-Anderson, Judith ; Kozikowski, Alan P. / Novel conformationally constrained tropane analogues by 6-endo-trig radical cyclization anti stille coupling - Switch of activity toward the serotonin anti/or norepinephrine transporter. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 10. pp. 2064-2071.
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N2 - A novel class of tricyclic tropane analogues has been synthesized by making use of radical cyclization technology in combination with the Stille coupling reaction. As hybrids between tropanes and quinuclidines, these tropaquinuclidines represent a significant structural departure from many of the other classes of tropane ligands synthesized to date. This structure class is characterized by the boat conformation of the tropane ring and the orientation of the additional bridge (and therefore of the nitrogen lone pair) together with the unusual placement of the aromatic moiety. All compounds were tested for their ability to inhibit monoamine reuptake under identical conditions. The ability to inhibit reuptake of dopamine in comparison to cocaine is generally decreased in this series but for one compound. (1S,3R,6S)-(Z)-9-(thienylmethylene)-7-azatricyclo[4.3.1.0]decane- 2β-carboxylic acid methyl ester (5h) exhibits reasonable activity at the dopamine transporter (DAT) (K(i) = 268 nM) and good activity at the norepinephrine transporter (NET) (K(i) = 26 nM). The potency and selectivity shown by some of these ligands for the NET, serotonine transporter (SERT), or NET/SERT is striking, particularly in view of the displacement of the aromatic ring in this series from its usual position at C-3 in the WIN analogues. Thus, (1S,3R,6S)-(Z)-9-(4-biphenylylmethylene)-7- azatricyclo[4.3.1.0]decane-2β-carboxylic acid methyl ester (5a) is a selective inhibitor of norepinephrine reuptake (K(i) = 12 nM). Its p-methoxy analogue 5c is a mixed inhibitor of norepinephrine and serotonin reuptake (K(i) = 187 nM at the NET and 56 nM at the SERT). The most active and selective compound we found in the present series is compound 8b [(1S,3R,6S)- 2-(acetoxymethyl)-(Z)9-(3,4-dichlorophenylmethylene)-7- azatricyclo[4.3.1.0]decane]. This compound is a potent (K(i) = 1.6 nM) and selective inhibitor of serotonin reuptake into rat midbrain synaptosomes. Its selectivity is about 400-fold over the NET and about 1000-fold over the DAT. The results of this study further demonstrate the possibility of tuning the selectivity of tropane analogues toward the SERT or NET binding site. The ligands disclosed herein provide additional pharmacological tools of use in attempting to correlate structure and transporter selectivity with in vivo studies of behavioral outcomes.

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