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

Abstract

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.

Design and Synthesis of 2- and 3-Substituted-3-phenylpropyl Analogs of 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(Diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine: Role of Amino, Fluoro, Hydroxyl, Methoxyl, Methyl, Methylene, and Oxo Substituents on Affinity for the Dopamine and Serotonin Transporters

“…13 Recently, SERT and NET have also been thought to play prominent roles in cocaine addiction. [14][15][16][17][18][19][20][21][22][23][24] Cocaine binds to DAT and SERT with moderate affinity (K i = 341 and 129 nM, respectively), 15 and blocks the reuptake of [ 3 H]DA and [ 3 H]5-HT (IC 50 = 478 and 304 nM, respectively). 12,18 In behavioral intervention and knock-out mice experiments, the serotonergic system has been found to influence the reinforcing effects of cocaine.…”

“…[14][15][16][17][18][19][20][21][22][23][24] Cocaine binds to DAT and SERT with moderate affinity (K i = 341 and 129 nM, respectively), 15 and blocks the reuptake of [ 3 H]DA and [ 3 H]5-HT (IC 50 = 478 and 304 nM, respectively). 12,18 In behavioral intervention and knock-out mice experiments, the serotonergic system has been found to influence the reinforcing effects of cocaine. 14,[25][26][27] In contrast to the extensive structure-activity relationship (SAR) studies for DAT-selective ligands, fewer SAR studies have been focused on the discovery and development of ligands with a variety of transporter selectivity for both DAT and SERT.…”

Design and Synthesis of Promiscuous High-Affinity Monoamine Transporter Ligands: Unraveling Transporter Selectivity

“…1 Cocaine binds with moderate and roughly equal affinities to dopamine transporters (DATs) and serotonin transporters (SERTs), which are monoamine transporters (Ki ) 341 ( 25, 129 ( 9, and 13 038 ( 983 nM for DAT, SERT, and norepinephrine transporter (NET) binding, respectively, using [ 125 I]RTI-55 for DAT and SERT, and [ 3 H]nisoxetine for NET). 2 Cocaine inhibits the presynaptic reuptake of neurotransmitters, such as dopamine (DA), serotonin (5-HT), and norepinephrine (NE) (e.g., [ 3,4 However, the main target for cocaine has been considered to be the dopamine transporter (DAT). The mesolimbic dopaminergic system has been said to mediate reinforcement and the dependence-producing properties of abused drugs, 3,[5][6][7][8] and drug-induced changes in this system may be one of the factors that can drive the compulsive use of cocaine.…”

Discovery of novel conformationally constrained tropane-based biaryl and arylacetylene ligands as potent and selective norepinephrine transporter inhibitors and potential antidepressants

“…Previously, we reported two classes of molecules, namely conformationally constrained tropanes and piperidine-based nocaine/modafinil hybrid ligands, as potent NET inhibitors. [11][12][13][14] To further explore the structure-activity relationships of conformationally constrained tropanes, a number of new biaryl and arylacetylene analogs were designed, synthesized and their monoamine transporter activity tested. To gain insights into their potential applications for the treatment of depression, we have also investigated the binding affinity of these compounds at the muscarinic receptor in continuation of our previous work, and the results will be discussed herein.…”

“…The key intermediates 2 and 4 were prepared in moderate yields by the Stille coupling of the vinylstannane 1 with 1,4-diiodobenzene or 2,5-diiodothiophene, utilizing previously reported procedures. 11,12 The subsequent Suzuki coupling of the iodides 2 and 4 with substituted phenylboronic acids or heteroarylboronic acids in the presence of Pd(OAc) 2 as the catalyst provided the desired biaryl analogs 3a-i and 5a-b in moderate to high yields. Our synthesis of the arylacetylene ligands makes use of the Sonogashira coupling reaction.…”