N-Substituted Analogs of 2β-Carbomethoxy-3β-(4‘-iodophenyl)tropane (β-CIT) with Selective Affinity to Dopamine or Serotonin Transporters in Rat Forebrain

Abstract

This report concerns the synthesis and chemical characterization of novel series of N-substituted 2 beta-carbomethoxy-3 beta-(4'-iodophenyl)tropane (beta-CIT, 2) analogs and their neuropharmacological evaluation for affinity at dopamine (DAT), serotonin (5-HTT), and norepinephrine membrane transporters in rat brain tissue. N-Substituted analogs of beta-CIT with a 2 beta-carbomethoxy ester moiety showed lower DAT affinity than beta-CIT for the DAT, and some were more selective for the 5-HTT over the DAT. 2 beta-Carbomethoxy(iodophenyl)nortropane analogs of beta-CIT with the N-substituents difluoroethyl, mesoxypropyl, iodopropyl, and methylpropionyl all yielded > 10-fold lower DAT affinity than beta-CIT itself, whereas the N-(fluoropropyl)-2 beta- isopropyl ester analog (1) of beta-CIT exceeded beta-CIT (2, an N-methyl-2 beta-carbomethoxy ester) in DAT affinity. Several N-haloalkyl-substituted beta-CIT analogs yielded high 5-HTT affinity (Ki < 0.6 nM), ranking: N-fluoropropyl (5) > N-chloropropyl (4) > or = N-bromopropyl (3) > beta-CIT (2) > N-3'-phtalimidopropyl (11), with particularly high (ca. 30-fold) 5-HTT-over-DAT selectivity found in the N-fluoropropyl (5) and N-fluoroethyl (6) compounds, compared to only 3.o-fold 5-HTT selectivity in beta-CIT itself. Highly 5-HTT selective agents such as 5 and 6 may be useful as brain-imaging ligands for serotonin neurons or as mood-elevating drugs, while the high affinity and selectivity for the DA transporter found in N-(fluoropropyl)-2 beta-(carboxyisopropyl)-3 beta-(4'-iodophenyl)-nortropane (1) and N-(fluoropropyl)-2 beta-carboxymethoxy-3 bet-(4'-iodophenyl)nortropane (FP-beta-CIT, 5) support their use as improved markers for DA neurons.

Distinct Molecular Recognition of Psychostimulants by Human andDrosophilaSerotonin Transporters

“…Similar van der Waals radii of the bromine and methyl substituent could explain the similarity in potency. This steric constraint has been observed with other cocaine derivatives at biogenic amine transporters (Neumeyer et al, 1996). Interestingly, our CoMFA models do not suggest a significant role for the charge associated with the amine nitrogen in contributing to potency.…”

“…All other chemicals were purchased from Sigma-Aldrich or Fischer Scientific (Pittsburgh, PA) and were of the highest grade available. 3-Phenyltropane analogs RTI-142 and RTI-121 (Neumeyer et al, 1994), RTI-55 and RTI-112 (Carroll et al, 1994), ␤-CFT (Neumeyer et al, 1996), RTI-32 (Holmquist et al, 1996), RTI-31 (Carroll et al,1995), RTI-83 (Blough et al, 1996), and RTI-311 (Scheffel et al, 1997) were synthesized as described previously. Substituted amphetamines were synthesized using conventional methodologies and their structures confirmed with NMR, mass spectrometry, and elemental analysis, all of which matched expected criteria.…”

Pharmacological Characterization of (E)-N-(4-Fluorobut-2-enyl)-2β-carbomethoxy-3β-(4′-tolyl)nortropane (LBT-999) as a Highly Promising Fluorinated Ligand for the Dopamine Transporter

“…The IC 50 values of GBR12935 and PE2I versus LBT-999 were 2.4 and 18 nM, respectively, and we did not find competition (IC 50 Ͼ 1 M) between LBT-999 and several serotonin transporter ligands [citalopram, paroxetine, and N,N-dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine] as well as norepinephrine transporter ligands (nisoxetine and desipramine). This selectivity is higher than that observed in vitro for other DAT ligands from the chemical tropane family such as FPCIT (Neumeyer et al, 1996), FPCBT (Chaly et al, 2004), CFT (Meltzer et al, 1993), FPCT (Goodman et al, 1997), and FECNT (Goodman et al, 2000). The selectivity of LBT-999 as indicated from the in vitro binding data on rat brain was clearly confirmed in the postmortem human autoradiographic study in which it bound highly to the caudate-putamen and only weakly to the thalamus and neocortical areas, as already observed for PE2I (Hall et al, 1999).…”

“…Its in vitro pharmacological properties on rat striatal membranes are very close to those of PE2I . It binds to a single high-affinity site with a moderate affinity (9 nM) closely related to that of other fluorinated tropane derivatives such as FPCIT (Neumeyer et al, 1996), FPCBT (Chaly et al, 2004), CFT (Meltzer et al, 1993), FPCT (Goodman et al, 1997), FECNT (Goodman et al, 2000), and PE2I and has a very high selectivity for the DAT. The IC 50 values of GBR12935 and PE2I versus LBT-999 were 2.4 and 18 nM, respectively, and we did not find competition (IC 50 Ͼ 1 M) between LBT-999 and several serotonin transporter ligands [citalopram, paroxetine, and N,N-dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine] as well as norepinephrine transporter ligands (nisoxetine and desipramine).…”

Synthesis and amine transporter affinities of novel phenyltropane derivatives as potential positron emission tomography (PET) imaging agents

“…N-(fluoroalkyl)Phenyltropane 12 was prepared by alkylation of 10 with fluoropropyl bromide according to previously reported procedures. 40,41 Attempts to treat the acid chlorides of 3 or 4 with 2-(ptoluylsulfonyl)ethanol failed to yield desired tosylates 17 and 18. However, 17 and 18 were readily prepared by treatment of alcohols 15 and 16 with p-toluenesulfonyl chloride and N,N,N 0 ,N 0 -tetramethyl-1,6-hexanediamine in acetonitrile at 0-5°C for 3 h (see Scheme 3).…”