131,300 ± 3001,100 ± 2001,400 ± 300550 ± 8012 ± 331 ± 1127 ± 1063 ± 275.24.7 3,4-dichloroisobutylh1.0 ± 0.531 ± 115.5 ± 1.313 ± 31,600 ± 100450 ± 401,100 ± 300290 ± 6025 ± 9120 ± 309.0 ± 1.219 ± 325.01.6 3,4-dichloroisobutylch36.6 ± 0.944 ± 1213 ± 445 ± 41,300 ± 2001,500 ± 3001,400 ± 5002,400 ± 700190 ± 60660 ± 13028 ± 3100 ± 1929.02.2 4-methoxyisobutylh52 ± 16770 ± 22025 ± 9400 ± 1202,800 ± 600950 ± 1903,500 ± 5001,200 ± 3003,100 ± 20016,000 ± 2,000410 ± 901,600 ± 40060.016.0 3-methoxyisobutylh22 ± 5950 ± 19035 ± 12140 ± 204,200 ± 4003,800 ± 6002,700 ± 8002,600 ± 3003,800 ± 50012,000 ± 2,300330 ± 401,400 ± 90170.09.4 4-isopropylisobutylh3,300 ± 600>6,5004,000 ± 400>9,1003,300 ± 6001,700 ± 5004,700 ± 7001,700 ± 1002,500 ± 6003,200 ± 6007,100 ± 1,800>8,7000.761.8 hcoch3h370 ± 70190 ± 507,800 ± 1,200>9,7002,700 ± 400220 ± 307.31.2 ɑh = equivalent overlay of structure sharing functional group bco2ch3 (i.e. cooch3) = equivalent overlay of structure sharing functional group cch3 = equivalent overlay of structure sharing functional group dpossible typographical error in original source; e.g. 2,100 ± 900 or 900 ± 210 restricted rotational analogs of methylphenidate (quinolizidines) two of the compounds tested, the weakest two @ dat & second to the final two on the table below, were designed to elucidate the necessity of both constrained rings in the efficacy of the below series of compounds at binding by removing one or the other of the two rings in their entirety. the first of the two retain the original piperidine ring had with methylphenidate but has the constrained b ring that is common to the restricted rotational analogues thereof removed. the one below lacks the piperdine ring native to methylphenidate but keeps the ring that hindered the flexibility of the original mph conformation. though their potency at binding is weak in comparison to the series, with the potency shared being approximately equal between the two; the latter compound (the one more nearly resembling the substrate class of dopaminergic releasing agents similar to phenmetrazine) is 8.3-fold more potent @ da uptake. binding assaysg of rigid methylphenidate analogues compoundɑ r & x substitution(s) ki (nm)@ dat with win 35,065-2 nh@ dat with win 35,065-2 ki (nm) or% inhibition@ net with nisoxetine nh@ net with nisoxetine ki (nm) or% inhibition@ 5-htt with citalopram nh@ 5-htt with citalopram da uptakeic50 (nm) selectivitycitalopram / win 35,065-2 selectivitynisoxetine / win 35,065-2 selectivitycitalopram / nisoxetine cocaine—156 ± 111.03 ± 0.011,930 ± 3600.82 ± 0.05306 ± 131.12 ± 0.15404 ± 262.0120.16 methylphenidate—74.6 ± 7.40.96 ± 0.08270 ± 230.76 ± 0.0614 ± 8%f—230 ± 16>1303.6>47 3′,4′-dichloro-mph—4.76 ± 0.622.07 ± 0.05ndh—667 ± 831.07 ± 0.047.00 ± 140140—— —6,610 ± 4400.91 ± 0.0111%b—3,550 ± 701.79 ± 0.558,490 ± 1,8000.54>0.76<0.7 h76.2 ± 3.41.05 ± 0.05138 ± 9.01.12 ± 0.205,140 ± 6701.29 ± 0.40244 ± 2.5671.837 3′,4′-dicl3.39 ± 0.771.25 ± 0.2928.4 ± 2.51.56 ± 0.80121 ± 171.16 ± 0.3111.0 ± 0.00368.44.3 2′-cl480 ± 461.00 ± 0.092,750; 58%b0.961,840 ± 701.18 ± 0.061,260 ± 2903.85.70.67 —34.6 ± 7.60.95 ± 0.18160 ± 181.28 ± 0.12102 ± 8.21.01 ± 0.0287.6 ± 0.353.04.60.64 ch2oh2,100 ± 6970.87 ± 0.09ndh—16.2 ± 0.05%f—10,400 ± 530>4.8—— ch37,610 ± 8001.02 ± 0.038.3%b—11 ± 5%f—7,960 ± 290>1.3≫0.66— d r=och3, x=h570 ± 490.94 ± 0.102,040; 64 ± 1.7%f0.7314 ± 3%f—1,850 ± 160>183.6>4.9 r=oh, x=h6,250 ± 2800.86 ± 0.0323.7 ± 4.1%b—1 ± 1%f—10,700 ± 750≫1.6>0.80— r=oh, x=3′,4′-dicl35.7 ± 3.21.00 ± 0.09367 ± 421.74 ± 0.872,050 ± 1101.15 ± 0.12ndh57105.6 h908 ± 1600.88 ± 0.054030; 52%b1.045 ± 1%f—12,400 ± 1,500≫114.4≫2.5 3′,4′-dicl14.0 ± 1.21.27 ± 0.20280 ± 760.68 ± 0.0954 ± 2%f—ndh~71020~36 r=oh, x=h108 ± 7.00.89 ± 0.10351 ± 850.94 ± 0.2712 ± 2%f—680 ± 52>933.3>28 r=oh, x=3′,4′-dicl2.46 ± 0.521.39 ± 0.2027.9 ± 3.50.70 ± 0.011681.02ndh68116.0 r=och3, x=h10.8 ± 0.80.97 ± 0.0763.7 ± 2.80.84 ± 0.042,070; 73 ± 5%f0.9061.0 ± 9.31905.932 r1=ch3, r2=h178 ± 281.23 ± 0.09694 ± 650.88 ± 0.134271.393682.43.90.62 r1=h, r2=ch3119 ± 201.17 ± 0.1276.0 ± 120.88 ± 0.062431.172482.00.643.2 —175 ± 8.01.00 ± 0.041,520 ± 1200.97 ± 0.0619 ± 4%f—ndh>578.69>6.6 r=ch2ch3, x=h27.6 ± 1.71.29 ± 0.05441 ± 491.16 ± 0.192,390; 80%f1.12ndh87155.8 r=ch2ch3, x=3′,4′-dicl3.44 ± 0.021.90 ± 0.05102 ± 191.27 ± 0.10286 ± 471.30 ± 0.10ndh83302.8 r=ch2ch3, x=h5.51 ± 0.931.15 ± 0.0360.8 ± 9.60.75 ± 0.073,550; 86%f0.95ndh6401158 r=ch2ch3, x=3′,4′-dicl4.12 ± 0.951.57 ± 0.0098.8 ± 8.71.07 ± 0.07199 ± 171.24 ± 0.00ndh48242.0 —6,360 ± 1,3001.00 ± 0.0436 ± 10%c—22 ± 7%f—8,800 ± 870>1.6—— i —4,560 ± 1,1001.10 ± 0.09534 ± 210c0.96 ± 0.0853 ± 6%f—1,060 ± 115~2.20.12~19 r1=ch2oh, r2=h, x=h406 ± 41.07 ± 0.08ndh—31.0 ± 1.5%f—1,520 ± 15>25—— r1=ch2och3, r2=h, x=h89.9 ± 9.40.97 ± 0.04ndh—47.8 ± 0.7%f—281 ± 19~110—— r1=ch2oh, r2=h, x=3′,4′-dicl3.91 ± 0.491.21 ± 0.06ndh—276; 94.6%f0.8922.5 ± 1.471—— r1=h, r2=co2ch3, x=3′,4′-dicl363 ± 201.17 ± 0.41ndh—2,570 ± 5801.00 ± 00.1317 ± 467.1—— r1=co2ch3, r2=h, x=2′-cl1,740 ± 2000.98 ± 0.02ndh—22.2 ± 2.5%f—2,660 ± 140>5.7—— ɑcompounds tested as hydroclhoride (hcl) salts, unless otherwise noted. b% inhibition caused by 5μm c% inhibition caused by 10μm, as assayed by sri dtested as free base eassayed by sri (appropriate correction factor applied.) f% inhibition of 10μm compound. gvalues expressed as x ± sem of 2—5 replicate tests. (if no sem shown, value is for an n of 1.) hnot determined icf. phenmetrazine & derivatives various mph congener affinity values inclusive of norepinephrine & serotonin values for dl-threo-methylphenidate derivatives are the mean (s.d.) of 3—6 determinations, or are the mean of duplicate determinations. values of other compounds are the mean—s.d. for 3—4 determinations where indicated, or are results of single experiments which agree with the literature. all binding experiments were done in triplicate. binding and uptake ic50 (nm) values for mat. compound da da uptake ne 5ht methylphenidate84 ± 33153 ± 92514 ± 74>50,000 o-bromomethylphenidate880 ± 316—20,000— m-bromomethylphenidate4 ± 118 ± 1120 ± 63,800 p-bromomethylphenidate21 ± 345 ± 1931 ± 72,600 p-hydroxymethylphenidate125263 ± 74270 ± 6917,000 p-methyloxymethylphenidate42 ± 24490 ± 27041011,000 p-nitromethylphenidate180—3605,900 p-iodomethylphenidate26 ± 14—321,800ɑ m-iodo-p-hydroxymethylphenidate42 ± 21195 ± 197370 ± 645,900 n-methylmethylphenidate1,400—2,80040,000 d-threo-methylphenidate33—244 ± 142>50,000 l-threo-methylphenidate540—5,100>50,000 dl-erythro-o-bromomethylphenidate10,000—50,000— cocaine120313 ± 1602,100190 win 35,42813—53072 nomifensine29 ± 16—15 ± 21,300ɑ mazindol9 ± 5—3 ± 292 desipramine1,400—3.5200 fluoxetine3,300—3,4002.4 ɑdenotes that preparation of membrane and results extrapolated therefrom originated from frozen tissue, which is known to change results when interpreting against fresh tissue experiments. p-hydroxymethylphenidate displays low brain penetrability, ascribed to its phenolic hydroxyl group undergoing ionization at physiological ph.