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.
A series of novel conformationally constrained tricyclic tropane derivatives containing a biaryl moiety, (Z)-9-(biarylylmethylene)-7-azatricyclo[4.3.1.0(3,7)]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 K(i) 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 (K(i) = 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 Ar(1) displays a high activity (K(i) = 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
J
Drug Discovery Program, Department of Neurology, Georgetown University Medical Center, 3970 Reservoir Road, NW, Washington, DC 20057-2197, USA.
Zhang
Ao
A
Kläss
Thomas
T
Johnson
Kenneth M
KM
Wang
Cheng Z
CZ
Ye
Yan Ping
YP
Kozikowski
Alan P
AP
D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D002352:Carrier Proteins / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008968:Molecular Conformation; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D027981:Symporters / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C474579:9-(2-(5-(4-methoxyphenyl)thienyl)methylene)-7-azatricyclo(4.3.1.0(3,7))decane-10-carboxylic acid methyl ester; C474578:9-(4-(3,4-dichlorophenyl)benzylidene)-7-azatricyclo(4.3.1.0(3,7))decane-10-carboxylic acid methyl ester; C474577:9-(4-(4-methoxyphenyl)benzylidene)-7-azatricyclo(4.3.1.0(3,7))decane-10-carboxylic acid methyl ester; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D006575:Heterocyclic Compounds, 3-Ring; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; C493216:Slc6a3 protein, rat; C493232:Slc6a4 protein, rat; D027981:Symporters; D014326:Tropanes; D012701:Serotonin; D004298:Dopamine; D009638:Norepinephrine