(nm) bic50 values for displacement of win 35428 cic50 values for displacement of citalopram dthe standard ki value for the displacement of gbr 12935, paroxetine, and nisoxetine were 27 ± 2, 3 ± 0.2, and 80 ± 28 nm, respectively, for these experiments 3β-(4-alkylthiophenyl)nortropanes structure compound r1 r2 inhibition of win 35,428@ datic50 (nm) inhibition of paroxetine@ 5-httki (nm) inhibition of nisoxetine@ netki (nm) net/dat(uptake ratio) net/5-htt(uptake ratio) see 7a—7h table 7ach3ch39 ± 30.7 ± 0.2220 ± 1024314 7bc2h5ch3232 ± 344.5 ± 0.51170 ± 3005260 8ach3h28 ± 60.19 ± 0.0121 ± 60.8110 8bc2h5h177 ± 621.26 ± 0.05118 ± 130.794 9ach3fch2ch2ch2112 ± 23 ± 1960 ± 1009320 9bc2h5fch2ch2ch21,200 ± 20027 ± 2>2,000274 10ach3ch2=ch2ch271 ± 255.5 ± 0.82,000 ± 50028364 10bc2h5ch2=ch2ch21,100 ± 10047 ± 3>2,000243 11ach3ch3ch2ch274 ± 205.7 ± 0.61,200 ± 14016211 11bc2h5ch3ch2ch2900 ± 30049 ± 6>2,000241 bridged n-constrained phenyltropanes (fused/tethered) see: bridged cocaine derivatives & n8 tricyclic (2β—crossed-over) n8—to—3β replaced aryl linked (expansive front-bridged) cocaine analogues p-methyl aryl front & back n-bridged phenyltropanes u.s. patent 6,150,376 structures mentioned in us6150376 table of ki data. alternate 2d rendering of compound "42a" (from among the above 'bridged' phenyltropanes) to elucidate the potential overlaying structure of the place inhabited by the constrained nitrogen. compare jnj-7925476, tametraline and similar compounds. rti-242 activity at monoamine transporters: binding affinities & mat inhibition of bridged phenyltropanes ki (nm) compound #(s. singh's #) 2β=r mazindol binding da uptake 5-ht uptake ne uptake selectivity5-ht/da cocaineco2ch3375 ± 68423 ± 147155 ± 4083.3 ± 1.50.4 (–)-40(–)-12854.3 ± 10.260.3 ± 0.41.76 ± 0.235.24 ± 0.070.03 (+)-40(+)-12879 ± 19114 ± 281.48 ± 0.074.62 ± 0.310.01 (±)-40(±)-12861.7 ± 8.560.3 ± 0.42.32 ± 0.232.69 ± 0.120.04 29β62014208030—— 30β18649297.7—— 31β47.021128.5—— 29α4140201003920—— 30α396088506961150— 451296.86 ± 0.4324.0 ± 1.31.77 ± 0.041.06 ± 0.030.07 42a131an-bu4.00 ± 0.072.23 ± 0.1214.0 ± 0.62.99 ± 0.176.3 41a130an-bu17.2 ± 1.1310.2 ± 1.478.9 ± 0.915.0 ± 0.47.8 42b131bet3.61 ± 0.4311.3 ± 1.125.7 ± 4.34.43 ± 0.012.3 50a133an-bu149 ± 6149 ± 2810 ± 8051.7 ± 125.4 49a132an-bu13.7 ± 0.814.2 ± 0.1618 ± 873.84 ± 0.3543.5 (–)-41050016500189070900— (+)-41850027600463038300— (–)-597409050119004650— (+)-5677010500251004530— rti-4229/coc-242n8/2β-c(o)ch(co2me)ch2npara-chloro—7.67 ± 0.31ɑ226.54 ± 27.37b510.1 ± 51.4c— ɑvalue for displacement of win 35,428 binding @ dat bvalue for displacement of paroxetine binding to sert cvalue for displacement of nisoxetine from net fused tropane-derivatives as neurotransmitter reuptake inhibitors. singh notes that all bridged derivatives tested displayed 2.5—104 fold higher dat affinity than cocaine. the ones 2.8—190 fold more potent at dat also had increased potency at the other two mat sites (net & sert); net having 1.6—78× increased activity. (+)-128 additionally exhibited 100× greater potency @ sert, whereas 132a & 133a had 4—5.2× weaker 5-htt (i.e. sert) activity. front-bridged (e.g. 128 & 129) had a better 5-ht/da reuptake ratio in favor of sert, while the back-bridged (e.g. 130—133) preferred placement with dat interaction. u.s. patent 5,998,405 3,4-cl2 aryl front-bridged phenyltropanes fused tropane: neurosearch a/s, scheel-krüger et al. u.s. patent 5,998,405 frontbridged phenyltropane synthesis intermediate product compound #140 codecompoundda (μm)ne (μm)5-ht (μm) 1(1 s,2s,4s,7r)-2-(3,4-dichloro- phenyl)-8-azatricyclo- undecan-11 -one o-methyl-oxime0.0120.00200.0033 2(1 s,2s,4s,7r)-2-(3,4-dichloro- phenyl)-8-azatricyclo- undecan-11-one0.180.0350.0075 3(1 s,3s,4s,8r)-3-(3,4-dichloro-phenyl)-7-azatricyclo- decan-5-one o-methyl-oxime0.01600.00090.0032 4(1 s,2s,4s,7r)-2-(3,4-dichloro-phenyl)-8-azatricyclo- undecan-11-ol0.07500.00410.0028 5(1 s,3s,4s,8r)-3-(3,4-dichloro-phenyl)-7-azatricyclo- decan-5-one0.120.00520.0026 6(1 s,3s,4s,8r)-3-(3,4-dichloro- phenyl)-7-azatricyclo-decan-5-ol0.250.00740.0018 7(1s,3s,4s,8r)-3- (3,4-dichloro- phenyl)-7-azatricyclodec- 5-yl acetate0.210.00610.0075 8(1s,3s,4s,8r)-3-(3,4-dichlorophenyl)-5-methoxy-7- azatricyclodecane0.0220.00140.0001 1-chloroethyl chloroformate is used to remove n-methyl of trans-aryltropanes. 2° amine is reacted with br(ch2)nco2et. base used to abstract proton α- to co2et group and complete the tricyclic ring closure step (dieckmann cyclization). to make a different type of analog (see kozikowski patent above) remove n-me add ɣ-bromo-chloropropane allow for cyclization with k2co3 base and ki cat. c2 + c3 (side-chain) fused (carboxylate & benzene conjoined) nitrogen-front-bridged indole phenyltropane. (1r,2s,10r,12s)-15-methyl-15-azatetracyclo(10.2.1.02,10.04,9)pentadeca-4(9),5,7-trien-3-one c3 to 1′ + 2′ (ortho) tropane locant dual arene bridged parent compound of a series of spirocyclic cocaine benzoyl linkage modification analogs created by suzuki coupling method of ortho-substituted arylboronic acids and an enol-triflate derived from cocaine; which technically has the three methylene length of cocaine analogues as well as the single length which defines the phenyltropane series. note that the carbomethoxyl group is (due to constraints in synthetic processes used in the creation of this compound) alpha configured; which is not the usual, most prevalent, conformation favored for the pt cocaine-receptor binding pocket of most such sub-type of chemicals. the above and below depictions show attested compounds synthesized, additionally with variations upon the endo–exo isomerism of their structures. cycloalkane-ring alterations of the tropane ring system azanonane (outer ring extended) 3-phenyl-9-azabicyclononane derivatives to better elucidate the binding requirements at mat, the methylene unit on the tropane was extended by one to create the azanonane analogs. which are the beginning of classes of modifications that start to become effected by the concerns & influences of macrocyclic stereocontrol. despite the loosened flexibility of the ring system, nitrogen constrained variants (such as were created to make the bridged class of phenyltropanes) which might better fit the rigid placement necessary to suit the spatial requirements needed in the binding pocket were not synthesized. though front-bridged types were synthesized for the piperidine homologues: the trend of equal values for either isomers of that type followed the opposing trend of a smaller and lessened plasticity of the molecule to contend with a rationale for further constraining the pharmacophore within that scope. instead such findings lend credence to the potential for the efficacy of fusing the nitrogen on an enlarged tropane, as like upon the compounds given below. azanonane analoguesdisplacement of bound win 35428 structure compound #(s. singh) ki (nm) cocaine32 ± 5390 ± 220 win 35065-233 ± 17310 ± 220 146a4600 ± 510 146b5730 ± 570 146c3450 ± 310 146d3470 ± 350 14713900 ± 2010 azabornane (outer ring contracted) 3-phenyl-7-azabicycloheptane derivatives ring-contracted analogs of phenyltropanes did not permit sufficient penetration of the phenyl into the target binding site on mat for an affinity in the efficacious range. the distance from the nitrogen to the phenyl centroid for 155a was 4.2 and 155c was 5.0 å, respectively. (whereas troparil was 5.6 & compound 20a 5.5 angstroms). however piperidine homologues (discussed below) had comparable potencies. 2-exo-phenyl-7-azabicycloheptane:the non-carboxylic (and dat substrate, releasing agent) variant of exo-2-phenyl-7-azabicyclo(2.2.1)heptane-1-carboxylic acid (n.b. the carboxy in the latter shares the c1 tropane position with the two carbon nitrogen containing bridge; sharing in the leftmost (r) substitution of the above depiction & unlike the placement on the tropane for either the carbmethoxy or phenyl ring of the azabornane analogues given in this section)with the carboxy ester function removed the resultant derived compound acts as a dat substrate drug, thus an amphetaminergic releaser of mat & vmat, yet similar to phenyltropanes (that usually are only re-uptake ligands) cf. exp-561 & btq. azabornanes with longer substitutions at the 3β-position (benzoyloxys alkylphenyls, carbamoyls etc.) or with the nitrogen in the position it would be on the piperidine homologues (i.e. arrangements of differing locations for the nitrogens being either distal or proximal within the terms required to facilitate the framework of the compound to a correlative proportion, functional for the given moiety), were not synthesized, despite conclusions that the nitrogen to phenyl length was the issue at variance enough to be the interfering factor for the proper binding of the compressed topology of the azabornane. carroll, however, has listed benzoyloxy azabornanes in patents. azabornane analoguesdisplacement of bound win 35428 structure compound #(s. singh) ki (nm) cocaine32 ± 5390 ± 220 win 35065-233 ± 17310 ± 220 155a60,400 ± 4,800 155b96,500 ± 42 155c5,620 ± 390 155d18,900 ± 1,700 piperidine homologues (inner two-carbon bridge excised) piperidine homologues had comparable affinity & potency spreads to their respective phenyltropane analogues. without as much of a discrepancy between the differing isomers of the piperidine class with respect to affinity and binding values as had in the phenyltropanes. p-chloro & related (piperidine homologues of phenyltropanes) phenyltropane 4-aryl-3-carboalkoxy-piperidine analogues structure compound #(s. singh) x = para- / 4′-substitution r = 2-tropane position dat (ic50 nm)win 35428 binding displacement da (ic50 nm)da uptake selectivityuptake/binding cocainehco2me102 ± 9239 ± 12.3 (±)-166aclβ-co2ch353.7 ± 1.937.8 ± 7.90.7 (-)-166aclβ-co2ch324.8 ± 1.685.2 ± 2.63.4 (+)-166aclβ-co2ch31360 ± 1255090 ± 1723.7 (-)-167aclβ-co2oh75.3 ± 6.249.0 ± 3.00.6 (+)-167aclβ-co2oh442 ± 32—— (-)-168aclβ-co2oac44.7 ± 10.562.9 ± 2.71.4 (+)-168aclβ-co2oac928 ± 432023 ± 822.2 (-)-169aclβ-n-pr3.0 ± 0.58.3 ± 0.62.8 (-)-170ahβ-co2ch3769 ± 19—— (±)-166bclα-co2ch3197 ± 8—— (+)-166bclα-co2ch357.3 ± 8.134.6 ± 3.20.6 (-)-166bclα-co2ch3653 ± 38195 ± 80.3 (+)-167bclα-co2oh240 ± 18683 ± 472.8 (+)-168bclα-co2oac461 ± 11—— (+)-169bclα-n-pr17.2 ± 0.523.2 ± 2.21.3 heterocyclic n-desmethyl naphthyl & related (piperidine homologues of phenyltropanes) activity @ mat for piperidine homologues of phenyltropanes, including naphthyl derivatives structure compound # da uptake (nm)ic50 da uptake (nm)ki ne uptake (nm)ic50 ne uptake (nm)ki 5-htt uptake (nm)ic50 5-htt uptake (nm)ki uptake ratioda/5-ht (ki) uptake ratione/5-ht (ki) cocaine459 ± 159423 ± 147127 ± 4.1108 ± 3.5168 ± 0.4155 ± 0.42.70.69 fluoxetine>4500>2500193 ± 4.1176 ± 3.58.1 ± 0.77.3 ± 0.762424 2075 ± 9.169 ± 8.1101 ± 3.388 ± 2.9440 ± 30391 ± 270.180.23 623 ± 1.021 ± 0.9-34 ± 0.88.2 ± 0.37.6 ± 0.22.84.5 7>1000947 ± 135-241 ± 1.78.2 ± 0.37.6 ± 0.222.65.7 894 ± 9.687 ± 8.9-27 ± 1.6209 ± 17192 ± 160.450.14 9293 ± 6.4271 ± 5.9-38 ± 4.013 ± 0.712 ± 0.7233.2 1997 ± 8.690 ± 8.034 ± 2.530 ± 2.33.9 ± 0.53.5 ± 0.5268.6 10326 ± 1.2304 ± 1.1337 ± 37281 ± 30113 ± 4.3101 ± 3.83.02.8 14144 ± 20131 ± 18204 ± 5.6175 ± 4.8155 ± 3.9138 ± 3.50.951.3 15>1800>1700>1300>1100275 ± 39255 ± 37>6>4 16>1000964 ± 100>1200>1000334 ± 48309 ± 443.13.5 17213 ± 30187 ± 26399 ± 12364 ± 9.2189 ± 37175 ± 341.12.1 18184 ± 30173 ± 26239 ± 42203 ± 3667 ± 4.562 ± 4.12.83.3 distal-nitrogen 'dimethylamine' (piperidine-like cyclohexyl homologues of phenyltropanes) cf. fencamfamine radiolabeled radiolabel tropane: page 64. g.a. whitlock et al. table 1 potential sri pet and spect ligands. lbt-999, a radio-ligand. codesert ki (nm)net ki (nm)dat ki (nm)radiolabelin vivo studyrefs. 10.2102.229.911cnon-human primate 20.231.732.611cnon-human primate 30.05243.47123irat 40.08281318fnon-human primate 50.114502211crat, monkey ipt (n-3-iodoprop-(2e)-ene-2β-carbomethoxy-3β-(4′-chlorophenyl)tropane), can be radiolabeled with 123i or 125i and used as a ligand to map several mats n-4-fluorobut-2-yn-1-yl-2β-carbomethoxy-3β-phenyltropane (pr04.mz) often radiolabeled. jhc1-64. a fluorescent analog, similar in its long chain off of the nitrogen bridge similar to the transition metal phenyltropane types. transition metal complexes these compounds include transition metals in their heteroatomic conformation, unlike non-radiolabel intended chelates where their element is chosen for intrinsic affectation to binding and function, these are tagged on by a "tail" (or similar) with a sufficient spacer to remain separated from known binding properties and instead are meant to add radioactivity enough to be easily tracked via observation methods that utilize radioactivity. as for anomalies of binding within the spectrum of the under-written kinds just mentioned: other factors not otherwise considered to account for its relatively lower potency, "compound 89c" is posited to protrude forward at the aryl place on its moiety toward the mat ligand acceptor site in a manner detrimental to its efficacy. that is considered due to the steric bulk of the eight-position "tail" chelate substituted constituent, overreaching the means by which it was intended to be isolated from binding factors upon a tail, and ultimately nonetheless, interfering with its ability to bind. however, to broach this discrepancy, decreasing of the nitrogen tether at the eight position by a single methylene unit (89d) was shown to bring the potency of the analogous compound to the expected, substantially higher, potency: the n-methyl analog of 89c having an ic50 of 1.09 ± 0.02 @ dat & 2.47 ± 0.14 nm @ sert; making 89c upwards of thirty-three times weaker at those mat uptake sites. "transition metal" chelated phenyltropanes structure compound #(s. singh) x = para- / 4′-substitution configuration dat (ic50 nm)displacement of win 35428 5-htt (ic50 nm)citalopram selectivity5-htt/dat win 35428f-11.0 ± 1.0160 ± 2014.5 +2β-chelated phenyltropanes 73trodat-1ɑcl-r=13.9, s=8.42b-- 74trotec-1f-high affinity site = 0.15 ± 0.04clow affinity site = 20.3 ± 16.1c-- n-chelated phenyltropanes 89af2β5.99 ± 0.81124 ± 1720.7 89bf2α2960 ± 1575020 ± 18801.7 89c3,4-cl22β37.2 ± 3.4264 ± 167.1 89dcl-0.31 ± 0.03d-- ɑiupac: oct-2-yl]methyl]-(2-mercaptoethyl)amino]ethyl]amino]ethanethiolato-(3—)-n2, n2′, s2, s2′]oxo--technetium br- & s- isomer values are ki (nm) for displacement of ipt with technetium-99m replaced by rhenium cic50 (nm) values for displacement of win 35428 with ligand tricarbonyltechnetium replaced with rhenium. (ic50 for win 35428 were 2.62 ± 1.06 @ high affinity binding & 139 ± 72 @ low affinity binding sites) dki value for displacement of ipt radioligand. select annotations of above phenyltropanes can be grouped by "n substitution" "stereochemistry" "2-substitution" & by the nature of the 3-phenyl group substituent x. often this has dramatic effects on selectivity, potency, and duration,