- Biaryl analogues of conformationally constrained tricyclic tropanes as potent and selective norepinephrine reuptake inhibitors: Synthesis and evaluation of their uptake inhibition at monoamine transporter sites
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A series of novel conformationally constrained tricyclic tropane derivatives containing a biaryl moiety, (Z)-9-(biarylylmethylene)-7-azatricyclo[4.3.1.03,7]decanes, were synthesized and evaluated for their ability to inhibit reuptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) by the DA, 5-HT, and NE transporters. Most of the compounds containing a methoxycarbonyl substituent at C-10 exhibit moderate to high inhibitory activity at the NET but lower activity at the DAT and SERT. Among these new compounds, some potent, NET-selective ligands were identified. The p-methoxy derivative 11a has a Ki value of 39 nM for uptake inhibition at the NET and moderate to high selectivity over the SERT (100-fold) and the DAT (20-fold). Compound 11f exhibits a remarkable potency (Ki = 9.7 nM) at the NET and a 25-fold selectivity over both the SERT and the DAT. Analogue 23 containing a thiophene ring as a bioisosteric replacement of the phenyl ring Ar1 displays a high activity (Ki = 10.3 nM) for the NET and similar selectivity over the SERT (50-fold) and the DAT (37-fold). The selectivity profile of biaryl analogues differs from that of the monoaryl series, as most members of that series display excellent potency at and selectivity for the SERT (J. Med. Chem. 2002, 45, 1930). This finding suggests that the different shape and size of the lipophilic recognition pocket that encompasses the aryl ring(s) of these tropanes are major determinants of a ligand's transporter activity at either the NET or the SERT. Some of the compounds in this series may also be valuable in sorting out the contribution of the individual transporters to cocaine's reinforcing properties.
- Zhou, Jia,Zhang, Ao,Kl?ss, Thomas,Johnson, Kenneth M.,Wang, Cheng Z.,Ye, Yan Ping,Kozikowski, Alan P.
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- NOVEL COCAINE HAPTENS AND NANOFIBER-BASED COCAINE VACCINES
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Certain embodiments are directed to chemically defined self-adjuvanting cocaine vaccines composed of novel cocaine haptens and self-assembling peptide domains.
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- Tropane analogs
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The present invention provides compounds, specifically novel tropane analogs, capable of acting as inhibitors of reuptake of monoamines. In preferred embodiments, these compositions are selective inhibitors of serotonin and/or norepinephrine reuptake. Also provided herein are pharmaceutical compositions comprising novel tropane analogs and a pharmaceutically acceptable carrier, and methods for treating conditions in which inhibition of reuptake of monoamines is desired. The inventive compositions as described herein are also useful for medical therapy and diagnosis.
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Page/Page column 21-22; Sheet 3
(2010/02/15)
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- Novel conformationally constrained tropane analogues by 6-endo-trig radical cyclization anti stille coupling - Switch of activity toward the serotonin anti/or norepinephrine transporter
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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.
- Hoepping, Alexander,Johnson, Kenneth M.,George, Clifford,Flippen-Anderson, Judith,Kozikowski, Alan P.
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p. 2064 - 2071
(2007/10/03)
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