2,3-disubstituted 6-azabicyclo[3.2.1]octanes as novel dopamine transporter inhibitors

A series of cis and trans 3beta-aryl-2-carbomethoxy-6-azabicyclo[3.2.1]octanes, with different substitution at the para-position of the aryl group, were synthesized and examined for reuptake inhibition at the dopamine transporter (DAT). The potency for inhibition of DA reuptake was compared with that of cocaine to determine the significance of the replacement of the 8-azabicyclo[3.2.1]octane (tropane nucleus), displayed in cocaine, for the 6-azabicyclo[3.2.1]octane (normorphan framework). This bicyclic core structure constitutes a novel chemical scaffold in DAT inhibitor design, which may provide new insights into the 3D structure of the DAT and its interaction with cocaine and DA. Among these compounds, the trans-amine series 8 were the most potent ligands at the DAT. In particular, the normorphan analogue 8c (bearing a p-chloro substituent at the beta-aryl group, IC(50)=452 nM) displayed a potency that is in the same range as cocaine (IC(50)=459 nM) itself.     

Synthesis and biological evaluation of 1-azabicyclo-[3.2.1]octanes: new dopamine transporter inhibitors

The synthesis and biological activity of a series of 6-substituted 1-azabicyclo[3.2.1]octanes are described. 1-Azabicyclo[3.2.1]octanes represent a new class of compounds that exhibit monoamine transporter inhibitory activity highly dependent on the overall topology and the absolute stereochemistry of the molecule.     

Synthesis of dopamine transporter selective 3-[2-(diarylmethoxyethylidene)]-8-alkylaryl-8-azabicyclo[3.2.1]octanes

A series of 3-[2-(diarylmethoxyethylidene)]-8-alkylaryl-8-azabicyclo[3.2.1]octanes was synthesized and the binding affinities of the compounds were determined at the dopamine and serotonin transporters. The 8-phenylpropyl analogues 8a (K(i)=4.1 nM) and 8b (K(i)=3.7 nM) were the most potent compounds of the series with binding affinities 3 times greater than GBR-12909. In addition, 8a (SERT/DAT=327) was over 300-fold more selective for the dopamine transporter than the serotonin transporter.     

Synthesis and dopamine transporter binding affinities of 3alpha-benzyl-8-(diarylmethoxyethyl)-8-azabicyclo[3.2.1]octanes

A series of 3alpha-benzyl-8-(diarylmethoxyethyl)-8-azabicyclo[3.2.1]octanes was synthesized and the binding affinities of the compounds were determined at the dopamine transporter. The unsubstituted analogue 7b (K(i)=98nM) was the most potent compound of the series with binding affinity three-times greater than cocaine and only 5-fold less than GBR-12909. The structure-activity data for 7a-f suggests that these compounds may be binding at the dopamine transporter in a similar fashion to GBR 12909.     

Synthesis of dopamine transporter selective 3-diarylmethoxymethyl-8-arylalkyl-8-azabicyclo[3.2.1]octane derivatives

A series of diarylmethoxymethyltropane-GBR hybrid analogues with all three possible stereochemical orientations at C3 were synthesized and evaluated at dopamine and serotonin transporters. The 3alpha derivatives were found to be the most potent compounds with the 3alpha-di(4-fluorophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]octane 15b (Ki = 5 nM) being the most potent compound of the series. The corresponding 3-di(4-fluorophenyl)-methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]oct-2-ene 12b (Ki = 12 nM) was slightly less potent than the 3alpha-analogue, while the 3beta-di(4-fluorophenyl)methoxymethyl-8-(3-phenylpropyl)-8-azabicyclo[3.2.1]octane 23b (Ki = 78 nM) exhibited only modest affinity for the dopamine transporter. Only the 3alpha-analogue 15b (SERT/DAT = 48) exhibited higher SERT/DAT selectivity than GBR 12909. These results indicate that the dopamine transporter can tolerate some variability in proximity of the benzhydryl ether to the basic nitrogen atom of the tropane without loss in potency. In addition, the structure-activity data for these tropane-GBR 12909 hybrid analogues support previous findings that the stereochemical and conformational effects imparted by unsaturation at C3 are important for dopamine transporter selectivity over the serotonin transporter.     

Bicyclo[3.2.1]octanes: synthesis and inhibition of binding at the dopamine and serotonin transporters

Herein we report the synthesis of a series of bicyclo[3.2.1]octanes and their binding characteristics at the dopamine and serotonin transporters. The data confirm that a heteroatom at position 8 of the tropane nucleus is not a prerequisite for binding since the bicyclo[3.2.1]octanes prove potent inhibitors of both transporters. Therefore the three-dimensional topology of the ligand may be more important than specific functionality with respect to stereospecific binding at the acceptor site.     

Synthesis and biological activity of 2-carbomethoxy-3-catechol-8-azabicyclo[3.2.1]octanes

Cocaine inhibits the dopamine transporter and the consequent elevation of dopamine is thought to contribute to the addictive properties of cocaine. Tropane analogues of cocaine, targeted to the dopamine transporter (DAT), are a significant focus of drug design for cocaine addiction medications. Herein, we report the function of the ortho hydroxy substituents in dopamine with respect to the azabicyclo[3.2.1]octane skeleton. The introduction of the o-dihydroxyl functionality led to reduced binding potency at monoamine transporters, rather than enhanced interaction with the DAT. It is therefore likely that the binding site for these compounds on the DAT is not the same as that for dopamine. Notwithstanding the moderate potency of the free catechols (>100 nM), 7 manifested stimulant activity with a duration of effect that exceeded 4 h in a rat locomotor activity assay. Compound 10, a diacetoxy prodrug for 7, substituted fully for cocaine in a rat drug-discrimination paradigm and is now undergoing further investigation as a potential medication for cocaine abuse.     

Synthesis of 8-thiabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters

Cocaine is a potent stimulant of the central nervous system. Its reinforcing and stimulant properties have been associated with inhibition of the dopamine transporter (DAT) on presynaptic neurons. In the search for medications for cocaine abuse, we have prepared 2-carbomethoxy-3-aryl-8-thiabicyclo[3.2.1]octane analogues of cocaine. We report that this class of compounds provides potent and selective inhibitors of the DAT and SERT. The selectivity resulted from reduced activity at the SERT. The 3beta-(3,4-dichlorophenyl) analogue inhibits the DAT and SERT with a potency of IC(50)=5.7 nM and 8.0 nM, respectively. The 3-(3,4-dichlorophenyl)-2,3-unsaturated analogue inhibits the DAT potently (IC(50)=4.5 nM) and selectively (>800-fold vs SERT). Biological enantioselectivity of DAT inhibition was limited for both the 3-aryl-2,3-unsaturated and the 3alpha-aryl analogues (2-fold), but more robust (>10-fold) for the 3beta-aryl analogues. The (1R)-configuration provided the eutomers.     

Synthesis and nicotinic acetylcholine receptor binding affinities of 2- and 3-isoxazolyl-8-azabicyclo[3.2.1]octanes

A series of epiboxidine homologues, 2- and 3-isoxazole substituted 8-azabicyclo[3.2.1]octane derivatives was synthesized and evaluated as potential ligands for neuronal nicotinic acetylcholine receptors in [(3)H]cytisine labeled rat brain. The 2beta-isoxazolyl-8-azabicyclo[3.2.1]octane 9b (K(i)=3 nM) was the most potent compound of the series with a binding affinity twice that of nicotine. The 3beta-isoxazolyl-8-azabicyclo[3.2.1]octane 15b (K(i)=148 nM) exhibited moderate affinity while the corresponding 2alpha- and 3alpha-isomers exhibited micromolar binding affinity.     

Chlorophenylpiperazine analogues as high affinity dopamine transporter ligands

Selective σ₂ ligands continue to be an active target for medications to attenuate the effects of psychostimulants. In the course of our studies to determine the optimal substituents in the σ₂-selective phenyl piperazines analogues with reduced activity at other neurotransmitter systems, we discovered that 1-(3-chlorophenyl)-4-phenethylpiperazine actually had preferentially increased affinity for dopamine transporters (DAT), yielding a highly selective DAT ligand.     

The synthesis of bivalent 2beta-carbomethoxy-3beta-(3,4-dichlorophenyl)-8-heterobicyclo[3.2.1]octanes as probes for proximal binding sites on the dopamine and serotonin transporters

3-Aryltropanes have been widely explored for potential medications for remediation of cocaine abuse. Research has focused predominantly on 8-azatropanes and it is now well recognized that these compounds can be designed to manifest varied selectivity and potency for inhibition of the dopamine, serotonin, and norepinephrine uptake systems. We had reported that the 8-nitrogen atom present in the 3-aryltropanes is not essential for tropanes to bind to monoamine uptake systems. We demonstrated that compounds in which the amine had been exchanged for an ether or a thioether retained binding potency and selectivity. We have now designed bivalent compounds in which two tropane moieties are linked by an intervening chain. These 8-homo- and 8-heterotropane bivalent compounds allowed a search for adjacent tropane binding sites on the DAT as well as a further exploration of whether the binding sites for 8-azatropanes are the same as those for other 8-heterotropanes. A comparison of these compounds with their progenitor tropanes cast into doubt the existence of proximal binding sites on the DAT, and offered support for the existence of different binding sites for the 8-azatropanes compared with 8-oxa- and 8-thiatropanes. Indeed, 8-aza bivalent tropanes inhibited DAT with potency about 10-fold lower (DAT: IC50 = 31 nM) than their monovalent counterparts. Furthermore, bivalent ligands in which one or both of the tropanes was devoid of an amine suffered a further loss of inhibitory potency. We conclude that it is unlikely that there exist two tropane binding sites in close proximity to one another on either the DAT or SERT.     

N-8-Substituted benztropinamine analogs as selective dopamine transporter ligands

A series of N-8-substituted benztropinamines was synthesized and evaluated for binding at the dopamine (DAT), serotonin (SERT), norepinephrine (NET) transporters, and muscarinic M1 receptors. In general, the isosteric replacement of the C-3 benzhydrol ether of benztropine by a benzhydryl amino group was well tolerated at the DAT. However, for certain N-8 substituted derivatives, selectivity over muscarinic M1 receptor affinity was reduced.     

The synthesis and biological evaluation of 2-(3-methyl or 3-phenylisoxazol-5-yl)-3-aryl-8-thiabicyclo[3.2.1]octanes

Cocaine, a potent stimulant of the central nervous system, owes its reinforcing and stimulant properties to its ability to inhibit monoamine uptake systems such as the Dopamine Transporter (DAT), and the Serotonin Transporter (SERT) located on presynaptic neurons in the striatum. The search for pharmacotherapies for cocaine addiction has focused on the design of compounds that bind selectively to the DAT and manifest slow onset of stimulatory action with long duration of action. We had reported that 3-aryl-2-carbomethoxy-8-thiabicyclo[3.2.1]octanes are potent and selective inhibitors of the DAT. In this Letter we report on the effects of replacement of the 2-carbomethoy group by a 2-isoxazole. This new class of 8-thiabicyclo[3.2.1]octanes provides potent and selective inhibitors of the DAT. The 3β-aryl compounds are particularly potent inhibitors of DAT (IC₅₀ = 7-43 nM) with substantial selectivity versus inhibition of SERT.     

QSAR study and synthesis of new phenyltropanes as ligands of the dopamine transporter (DAT)

The dopamine transporter (DAT) plays a pivotal role in the regulation of dopamine neurotransmission, and is involved in a number of physiological functions and brain disorders. Furthermore the DAT analysis by molecular imaging techniques is a useful tool for the diagnosis and follow up treatment of diseases involving the DAT. In order to predict the affinity of new derivatives for the DAT, different QSAR molecular modeling models based on cocaine were compared. We have evaluated in these models tropane derivatives synthesized with original synthons which coupled properties of both fluorine and iodine atoms. One compound showed a high in vitro affinity and selectivity for the DAT (K(i)=0.87±0.04 nM). This compound should be radiolabeled with radioiodine for further investigations by SPECT.     

[3-Azabicyclo[3.1.0]hex-1-yl]phenyl-benzenesulfonamides as selective dopamine D3 antagonists

A new class of azabicyclo[3.1.0]benzenesulfonamides is presented as selective dopamine D₃ antagonists together with SAR and selectivity data.     

Biomimetic synthesis of 2,3-dioxabicyclo [4,4,0] decanes as plant growth regulators

Naturally occurring derivatives of 2,3-dioxabicyclo [4,4,0] decane from Ecucalyptus grandis have been reported to possess a wide range of biological control in various plants including the parent one. The biogenetic type synthesis of these compounds have been discussed in this Paper.     

Novel aryloxy-8-azabicyclo[3.2.1]oct-3-enes with 5-HT transporter and 5-HT1A affinity

Joining aryl 8-azabicyclo[3.2.1]oct-3-enes with aryloxyethanes and aryloxypropanes produces novel series of compounds 11 and 12 with potent 5-HT-T affinity and moderately potent 5-HT(1A) affinity. Moreover, several of these compounds possess functional 5-HT(1A) antagonism. Optimal compounds are, 4-indolyloxyethane 21, 4-indolyloxypropanes 25, and 27, which possess potent 5-HT-T affinity (5-HT-T K(i): 21: 1.2nM, 25: 0.54nM, 27: 0.38nM) and good 5-HT(1A) affinity/antagonism (5-HT(1A)K(i), [(35)S]GTPgammaS: E(max) (%): 21: 111.1nM, 0%; 25: 173.2nM, 0%; 27: 107nM, 0%).     

Design, synthesis, and evaluation of hexahydrobenz[f]isoquinolines as a novel class of dopamine 3 receptor ligands

We previously identified hexahydrobenz[f]isoquinoline (4a) as a new class of dopamine 3 receptor (D(3)) ligand. Herein, we described the design, synthesis, and preliminary structure-activity relationships of new analogues of 4a as a novel class of D(3) ligands. Among these new analogues, compound 4 h is a potent D(3) ligand (K(i)=6.1 nM) and has a selectivity of 133-fold between D(3)- and D(2)-like receptors, and of 163-fold between D(3)- and D(1)-like receptors, respectively. Thus, compound 4 h represents a promising new lead compound for further design and optimization toward achieving highly potent and selective D(3) ligands.