± 4851231 ± 9124158.6 rti-274dfch2o(3′,4′-md-phenyl)β,αnh3.965.6214.4—— rti-287etco2meβ,αnme327168717,819—— 20cclco2meβ,αnme2.4 ± 0.2998 ± 12060.1 ± 2.441625.0 20emeco2meβ,αnme10.2 ± 0.084250 ± 422275 ± 2441727.0 bnco2meβ,αnme————— ɑu.s. patent 6,358,492bu.s. patent 7,011,813cu.s. patent 7,011,813du.s. patent 7,291,737 α,β stereochemistry ca 2112084 compoundda (μm)m.e.d. (mg/kg)dose (mg/kg)activityactivity (2r,3s)-2-(4-chlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclooctane0.39<15000 (2r,3s)-2-(carboxymethyl)-8-methyl-3-(2-naphthyl)-8-azabicyclooctane0.112500 (2r,3s)-2-(carboxymethyl)-8-methyl-3-(3,4-dichlorophenyl)-8-azabicyclooctane0.0160.2550++++ di-chloro; para- & meta- in tandem (α,β configured phenyltropanes) u.s. patent 2,001,047,028 compoundx2 groupconfig8da5-htne brasofensinecl2methyl aldoximeα,βnme——— tesofensinecl2ethoxymethylα,βnme65111.7 ns-2359 (gsk-372,475)cl2methoxymethylα,βnh——— fumaric acid salts (of α,β configured phenyltropanes) wo 2004072075, peters, dan; nielsen, elsebet oestergaard & olsen, gunnar m. et al., "novel 8-aza-bicyclooctane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors", published 2004-08-26, assigned to neurosearch as test compound da uptake ic50(μm) ne uptake ic50(μm) 5-ht uptake ic50(μm) (2r,3s)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclooctane fumaric acid salt0.0620.0350.00072 (2r,3s)-2-(naphthaleneoxymethane)-8-methyl-3-(3-chlorophenyl)-8-azabicyclooctane fumaric acid salt0.0620.150.0063 (2r,3s)-2-(2,3-dichlorophenoxymethyl)-8-h-3-(3-chlorophenyl)-8-azabicyclooctane fumaric acid salt0.100.0480.0062 (2r,3s)-2-(naphthlyloxymethane)-8-h-3-(3-chlorophenyl)-8-azabicyclooctane fumaric acid salt0.0880.0510.013 arene equivalent alterations η6-3β-(transition metal complexed phenyl)tropanes ×–substitution image of both the chromium & ruthenium benzene pi-symmetry facilitating pts.21b can be prepared from ferrocenes and perrhenate by a double ligand transfer (dlt) reaction. unlike metal complexed pts created with the intention of making useful radioligands, 21a & 21b were produced seeing as their η6-coordinated moiety dramatically altered the electronic character and reactivity of the benzene ring, as well as such a change adding asymmetrical molecular volume to the otherwise planar arene ring unit of the molecule. (cf. the dewar–chatt–duncanson model). in addition the planar dimension of the transition metal stacked arene becomes delocalized (cf. bloom and wheeler.). 21a was twice as potent as both cocaine and troparil in displacement of β-cft, as well as displaying high & low affinity ki values in the same manner as those two compounds. whereas its inhibition of da uptake showed it as comparably equipotent to cocaine & troparil. 21b by contrast had a one hundredfold decrease in high-affinity site binding compared to cocaine and a potency 10× less for inhibiting da uptake. attesting these as true examples relating useful effective applications for bioorganometallic chemistry. tricarbonyl-3β-chromium containing phenyltropane, having roughly twice the strength ki affinity as parent compound at same mean affect. the discrepancy in binding for the two benzene metal chelates is assumed to be due to electrostatic differences rather than their respective size difference. the solid cone angles, measured by the steric parameter (i.e. θ) is θ=131° for cr(co)3 whereas cp*ru was θ=187° or only 30% larger. the tricarbonyl moiety being considered equivalent to the cyclopenta dienyl (cp) ligand. diagram indicating the triflate, in bracket, superimposed as a direct connection between the η6 benzene containing its transition metal fixed upon the η5-penta-methyl (five-methyls) cyclopenta-dienyl (five sided ring) alongside the benzene in three dimension. displacement of receptor-bound win 35428 and inhibition of da uptake by transition metal complexes of 3β-phenyltropanes structure compound #(s. singh)systematic name ki (nm)ɑ ic50 (nm) selectivitybinding/uptake 21ac17 ± 15b224 ± 8341824.6 21bd2280 ± 18338901.7 cocaine32 ± 5388 ±22140512.6 troparil (11a)33 ± 17314 ± 22237311.3 ɑthe binding data fit a two-site model better than a one-site model bthe ki value for the one-site model was 124 ± 10 nm ciupac: tricarbonylchromium diupac: -ruthenium-(ii) triflate 3-(2-thiophene) and 3-(2-furan) u.s. patent 7,247,643 codecompoundda (μm)ne (μm)5-ht (μm) 1(2r,3s)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclooctanefumaric acid salt0.300.00190.00052 2(2r,3s)-2-(1-naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo-octane fumaric acid salt0.360.00360.00042 3(2r,3s)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-octane fumaric acid salt0.310.000900.00036 4(2r,3s)-2-(1-naphthyloxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-octane fumaric acid salt0.920.00300.00053 5(2r,3s)-2-(2,3-dichlorophenoxymethyl)-8-h-3-(2-thienyl)-8-aza-bicyclooctane fumaric acid salt0.0740.00180.00074 6(2r,3s)-2-(1-naphthyloxymethyl)-8-h-3-(2-thienyl)-8-aza-bicyclooctane fumaric acid salt0.190.00160.00054 thiophenyltropanes diaryl fluoxetine homologue, also: hanna et al. (2007) cf. the paroxetine homologue ptszient: 6/7-tropane position substituted 2β-carbomethoxy 6/7 substituted 6/7-substituted 2-carbomethoxy-phenyltropanes structure compound #(s. singh) substitution dat (ic50 nm)displacement of win 35428 5-htt (ic50 nm)citalopram selectivity5-htt/dat cocaineh65 ± 12-- 103a3β,2β, 7-ome3′,4′-cl286 ± 4.7884 ± 10010.3 103b3β,2β, 7-oh3′,4′-cl21.42 ± 0.0328.6 ± 7.820.1 103c3α,2β, 7-oh3′,4′-cl21.19 ± 0.161390 ± 561168 104a3β,2β, 6-oh4′-me215ɑ-- 104b3β,2α, 6-oh4′-me15310ɑ-- 104c3α,2β, 6-oh4′-me930ɑ-- 104d3α,2α, 6-oh4′-me7860ɑ-- ɑic50 value for displacement of mazindol. ic50 for cocaine 288 nm for displacement of mazindol 3-butyl 6/7 substituted 6/7-substituted 3-butyl-phenyltropanes structure compound #(s. singh) substituent ki nmdisplacement of mazindol binding ki nmda uptake selectivityuptake/binding cocaineh270 ± 0.03400 ± 201.5 121a7β-cn2020 ± 10710 ± 400.3 121b6β-cn3040 ± 4806030 ± 8802.0 121c7β-so2ph4010 ± 3108280 ± 13402.1 121d6β-so2ph4450 ± 4308270 ± 6901.8 121e7α-oh830 ± 40780 ± 600.9 121fh100 ± 1061 ± 100.6 121g7β-cn24000 ± 342032100 ± 85401.3 121h6β-cn11300 ± 154026600 ± 33302.3 121i7β-so2ph7690 ± 27707050 ± 4500.9 121j6β-so2ph4190 ± 7008590 ± 13602.0 121k7α-so2ph3420 ± 1100-- 121l7β-so2ph, 7α-f840 ± 2602520 ± 2903.0 121m7α-f200 ± 10680 ± 103.4 121n7β-f500 ± 10550 ± 1401.1 intermediate 6- & 7-position synthesis modified phenyltropanes 6/7-synthetic intermediates structure compound #(s. singh) substituent w substituent x substituent y substituent z (±)-122acnhhh (±)-122bhhchh (±)-122chchhh (±)-122dhhhch (±)-122eso2phhhh (±)-122fhhso2phh (±)-122ghso2phhh (±)-122hso2phfhh (±)-122ifso2phhh (±)-122jhhso2phf 8-tropane (bridgehead) position modified nortropanes (n-demethylated) ns2359 (gsk-372,475) it is well established that electrostatic potential around the para position tends to improve mat binding. this is believed to also be the case for the meta position, although it is less studied. n-demethylation dramatically potentiates net and sert affinity, but the effects of this on dat binding are insignificant. of course, this is not always the case. for an interesting exception to this trend, see the taxil document. there is ample evidence suggesting that n-demethylation of alkaloids occurs naturally in vivo via a biological enzyme. the fact that hydrolysis of the ester leads to inactive metabolites means that this is still the main mode of deactivation for analogues that have an easily metabolised 2-ester substituent. the attached table provides good illustration of the effect of this chemical transformation on mat binding affinities. n.b. in the case of both nocaine and pethidine, n-demethyl compounds are more toxic and have a decreased seizure threshold. selected ββ nortropanes code(s.s. #) xpara(unless position otherwise given inline) da 5ht ne rti-14275bf4.3968.618.8 rti-9875dnorɑ-rti-55i0.690.3611.0 rti-11075ccl0.624.135.45 rti-17375fet49.98.13122 rti-279norɑ-rti-280para-memeta-i5.98 ± 0.481.06 ± 0.1074.3 ± 3.8 rti-305norɑ-rti-360/11yethynyl1.24 ± 0.111.59 ± 0.221.8 ± 1.0 rti-307norɑ-rti-281/11zpropynyl6.11 ± 0.673.16 ± 0.33115.6 ± 5.1 rti-309norɑ-11tvinyl1.73 ± 0.052.25 ± 0.1714.9 ± 1.18 rti-330norɑ-11sisopropyl310.2 ± 2115.1 ± 0.97— rti-353para-etmeta-i330.54 ± 17.120.69 ± 0.07148.4 ± 9.15 ɑthe n-demethylated variant of (i.e. compound code-name after dash) n-demethylating various β,β p-hc-phenyltropanes n-me compound code#→n-demethylated derivativecompound code # para-x paroxetine win 35,428 nisoxetine 11 g→75f ethyl 28.4 → 8.13 55 → 49.9 4,029 → 122 11t→75i vinyl 9.5 → 2.25 1.24 → 1.73 78 → 14.9 11y→75n ethynyl 4.4 → 1.59 1.2 → 1.24 83.2 → 21.8 11r→75 g 1-propyl 70.4 → 26 68.5 → 212 3,920 → 532 11v→75k trans-propenyl 11.4 → 1.3 5.29 → 28.6 1,590 → 54 11w→75l cis-propenyl 7.09 → 1.15 15 → 31.6 2,800 → 147 11x→75 m allyl 28.4 → 6.2 32.8 → 56.5 2,480 → 89.7 11z→75o 1-propynyl 15.7 → 3.16 2.37 → 6.11 820 → 116 11s→75h i-propyl 191 → 15.1 597 → 310 75,000 → ? 11u→75j 2-propenyl 3.13 → 0.6 14.4 → 23 1,330? → 144 n-demethylating phenyltropanes to find a nri isomer 4′ 3′ ne da 5ht β,β me h 60 → 7.2 1.7 → 0.84 240 → 135 β,β f h 835 → 18.8 15.7 → 4.4 760 → 68.6 β,β cl h 37 → 5.45 1.12 → 0.62 45 → 4.13 β,α me h 270 → 9 10.2 → 33.6 4250 → 500 β,α f h 1200 → 9.8 21 → 32.6 5060 → 92.4 β,α cl h 60 → 5.41 2.4 → 3.1 998 → 53.3 β,α f me 148 → 4.23 13.7 → 9.38 1161 → 69.8 β,α me f 44.7 → 0.86 7.38 → 9 1150 → 97.4 "interest in net selective drugs continues as evidenced by the development of atomoxetine, manifaxine, and reboxetine as new net selective compounds for treating adhd and other cns disorders such as depression" (fic, et al. 2005). n-norphenyltropanes structure short name(s. singh) para-x datwin 35428 ic50 (nm) 5-httparoxetine ic50 (nm) netnisoxetine ic50 (nm) selectivity5-htt/dat selectivitynet/dat norcocaineh206 ± 29127 ± 13139 ± 90.60.7 75ah30.8 ± 2.3156 ± 884.5 ± 7.55.12.7 75bf4.39 ± 0.2068.6 ± 2.018.8 ± 0.715.64.3 75ccl0.62 ± 0.094.13 ± 0.625.45 ± 0.216.78.8 75di0.69 ± 0.20.36 ± 0.057.54 ± 3.190.510.9 75epara-i&2β-co2ch(ch3)21.06 ± 0.123.59 ± 0.27132 ± 53.4124 75fc2h549.9 ± 7.38.13 ± 0.30122 ± 120.22.4 75gn-c3h7212 ± 1726 ± 1.3532 ± 8.10.12.5 75hch(ch3)2310 ± 2115.1 ± 0.97-0.05- 75ich=ch21.73 ± 0.052.25 ± 0.1714.9 ± 1.181.38.6 75jc-ch3║ch223 ± 0.90.6 ± 0.06144 ± 120.036.3 75ktrans-ch=chch328.6 ± 3.11.3 ± 0.154 ± 160.041.9 75lcis-ch=chch331.6 ± 2.21.15 ± 0.1147 ± 4.30.044.6 75mch2ch=ch256.5 ± 566.2 ± 0.389.7 ± 9.60.11.6 75nch≡ch1.24 ± 0.111.59 ± 0.221.8 ± 1.01.317.6 75och≡cch36.11 ± 0.673.16 ± 0.33116 ± 5.10.519.0 75pɑ3,4-cl20.66 ± 0.241.4b-2.1- ɑthese values determined in cynomolgus monkey caudate-putamen bthe radioligand used for 5-htt was citalopram 2β-propanoyl-n-norphenyltropanes compound structure short name(s. singh) datrti-55 ic50 (nm) 5-httparoxetine ki (nm) netnisoxetine ki (nm) selectivity5-htt/dat selectivitynet/dat 79a0.07 ± 0.010.22 ± 0.162.0 ± 0.093.128.6 79b4.7 ± 0.5819 ± 1.45.5 ± 2.04.01.2 79c380 ± 1105.3 ± 1.03400 ± 2700.018.9 79d190 ± 17150 ± 505100 ± 2200.826.8 79e490 ± 12085 ± 164300 ± 11000.18.8 79f1.5 ± 1.10.32 ± 0.0610.9 ± 1.50.27.3 79g16 ± 4.90.11 ± 0.0294 ± 180.075.9 paroxetine homologues see the n-methyl paroxetine homologues cf. di-aryl phenyltropanes for another ssri approximated hybrid: the fluoxetine based homologue of the phenyltropane class. 2-(3,4-(methylenedioxy)phenoxy)methyl-norphenyltropane binding potencies compound structure short name(s. singh) stereochemistry datwin 35428 ic50 (nm) 5-httparoxetine ic50 (nm) netnisoxetine ic50 (nm) selectivity5-htt/dat selectivitynet/dat paroxetine-623 ± 250.28 ± 0.02535 ± 150.00040.8 r-81a2β,3β835 ± 90480 ± 2137400 ± 14000.644.8 r-81b2α,3β142 ± 1390 ± 3.42500 ± 2500.617.6 r-81c2β,3α3.86 ± 0.25.62 ± 0.214.4 ± 1.31.43.7 s-81d2β,3β1210 ± 33424 ± 1517300 ± 18000.314.3 s-81e2α,3β27.6 ± 2.455.8 ± 5.731690 ± 1502.061.2 s-81f2β,3α407 ± 3319 ± 1.81990 ± 1760.054.9 n-replaced (s,o,c) r-97a (above) & s-97b (below), both examples of interm. synth. prod. in the r/s-90 & 91 series of phenyltropanes; showing the decay of the benzene structure during the synthetic process preceding the creation of like-series of pts. the eight position nitrogen has been found to not be an exclusively necessary functional anchor for binding at the mat for phenyltropanes and related compounds. sulfurs, oxygens, and even the removal of any heteroatom, leaving only the carbon skeleton of the structure at the bridged position, still show distinct affinity for the monoamine transporter cocaine-target site and continue to form an ionic bond with a measurable degree of reasonable efficacy. compoundx2 groupconfig8da5-htne tropoxanecl,clco2me(racemic) β,βo3.36.5no data o-4210p-f3-methyl-5-isoxazoleβ,βs7.0>1000no data mid-synth stage in similar compound preparation as like to above. 8-oxa bridgehead replacements 8-oxanortropanes, binding inhibition using monkey caudate-putamen structure compound #(s. singh) para-(meta-) dat (ic50 nm)displacement of win 35428 5-htt (ic50 nm)citalopram selectivity5-htt/dat r/s-90ah>1000>1000- r/s-90bf54625804.7 r/s-90ccl1010710.7 r/s-90dbr22301.4 r/s-90ei7121.7 r/s-90f3,4-cl23.356.521.9 r-90g3,4-cl23.274.671.4 s-90h3,4-cl247581.2 r/s-91ah1990114405.7 r/s-91bf>1000>10000- r/s-91ccl28.581628.6 r/s-91dbr927630.7 r/s-91ei42721.7 r/s-91f3,4-cl23.0864.520.9 r-91g3,4-cl22.343113.2 s-91h3,4-cl256286051.1 8-carba bridgehead replacements 8-carba 3-aryl bicyclooctanes structure compound #(s. singh) dat (ic50 nm)displacement of win 35428 5-htt (ic50 nm)citalopram selectivity5-htt/dat r/s-98a7.1 ± 1.75160 ± 580726 r/s-98b9.6 ± 1.833.4 ± 0.63.5 r/s-98c14.3 ± 1.1180 ± 6512.6 n-alkyl compoundx2 groupconfig8datsertnet fp-β-cppitcl3′-phenylisoxazol-5′-ylβ,βnch2ch2ch2f--- fe-β-cppitcl(3′-phenylisoxazol-5′-yl)β,βnch2ch2f--- altropane (iacft)fco2meβ,βnch2ch=chf--- fecntico2meβ,βnch2ch2f--- rti-310 u.s. patent 5,736,123ico2meβ,βn-prn1.17-- rti-311ico2meβ,βnch2ch=ch21.79-- rti-312 u.s. patent 5,736,123ico2meβ,βnbun0.76-- rti-313 u.s. patent 5,736,123ico2meβ,βnch2ch2ch2f1.67-- ioflupane (fp-cit)123ico2meβ,βnch2ch2ch2f--- pe2imeco2meβ,βnch2ch=chi--- rti-251clco2meβ,βnch2co2et1.9310.1114 rti-252clco2meβ,βnch2ch2co2et2.5635.2125 rti-242clβ,β (bridged) -c(o)ch(co2me)ch2n7.67227510 bi- and tri-cyclic aza compounds and their uses. n-substituted 3β-phenylnortropanes(including n-phthalimidoalkyl analogues of β-cit) structure short name(s. singh) nitrogen side-chain(n8) datgbr 12935 ki (nm) 5-httparoxetine ki (nm) netnisoxetine ki (nm) selectivity5-htt/dat selectivitynet/dat cocaineh350 ± 80>10000>30000>28.6- gbr 12909-0.06 ± 0.0252.8 ± 4.4>20000880- win 3542811bh14.7 ± 2.9181 ± 21635 ± 11012.343.2 rti-5511eh1.40 ± 0.200.46 ± 0.062.80 ± 0.400.32 82ach2ch=ch222.6 ± 2.9ɑ---- 82bch2ch2ch343.0 ± 17.7ɑ---- 82cch2c6h558.9 ± 1.65b1073c-18.2- 82d(ch2)3c6h51.4 ± 0.2b133 ± 7c-95.0- 82e(ch2)5c6h53.4 ± 0.83b49.9 ± 10.2c-14.7- 83ach2ch2ch2f1.20 ± 0.2948.7 ± 8.41000040.68333 83bch2ch2f4.40 ± 0.3521.7 ± 8.3>100004.9- 84ach2ch2ch2f3.50 ± 0.390.110 ± 0.0263.0 ± 4.00.0318 84bch2ch2f4.00 ± 0.730.140 ± 0.0293.0 ± 17.00.0323.2 84cch2chf215.1 ± 3.79.6 ± 1.5>50000.6- 84dch2ch2ch2cl3.10 ± 0.570.32 ± 0.0696.0 ± 29.00.131.0 84ech2ch2ch2br2.56 ± 0.570.35 ± 0.08164 ± 470.164.1 84fch2ch2ch2i38.9 ± 6.38.84 ± 0.5350000.2128 84gch2...methylcyclopropane4.30 ± 0.871.30 ± 0.25198 ± 9.60.346.0 84hch2ch2ch2oh5.39 ± 0.212.50 ± 0.20217 ± 190.540.2 84ich2ch2(och3)26.80 ± 1.101.69 ± 0.09110 ± 7.70.216.2 84jch2co2ch311.9 ± 1.40.81 ± 0.1029.1 ± 1.00.072.4 84kch2con(ch3)212.2 ± 3.86.40 ± 1.70522 ± 1450.542.8 84lch2ch2ch2oms36.3 ± 2.117.3 ± 1.250000.5138 84mcoch(ch3)22100 ± 140102 ± 23>100000.05- 84n(ch2)2pht4.23 ± 0.480.84 ± 0.02441 ± 66.00.2104 84o(ch2)3pht9.10 ± 1.100.59 ± 0.0774.0 ± 11.60.068.1 84p(ch2)4pht2.38 ± 0.220.21 ± 0.02190 ± 18.00.0979.8 84q(ch2)5pht2.40 ± 0.170.34 ± 0.0360.0 ± 3.100.125.0 84r(ch2)8pht2.98 ± 0.300.20 ± 0.0275.0 ± 3.60.0725.2 84sdch2ch=ch-ch315 ± 175 ± 5400 ± 805.026.7 84tdch2c(br)=ch230 ± 5200 ± 40>10006.7- 84udch2ch=ch2i(e)30 ± 5960 ± 60295 ± 3332.09.8 84vdch2c≡ch14 ± 1100 ± 30>10007.1- 84wdch2c6h542 ± 12100 ± 17600 ± 1002.414.3 84xdch2c6h4-2-ch393 ± 19225 ± 40>10002.4- 85adpara-h113 ± 41100 ± 20>10000.9- 85bdpara-cl, meta-cl29 ± 450 ± 6500 ± 1201.717.2 85cdpara-me17 ± 7500 ± 30>100029.4- 85ddpara-ch(ch3)2500 ± 120450 ± 80>10000.9- 85edpara-n-c3h7500 ± 100300 ± 12750 ± 1600.61.5 ɑic50 for displacement of cocaine. ic50 for cocaine = 67.8 ± 8.7