A series of 3-(3′,4′-dichlorophenyl)-1-indanamine monoamine reuptake blockers have been synthesized in an effort to develop a compound that could be used as a maintenance therapy to treat cocaine abuse. Since the effects of cocaine on dopamine (DA) and serotonin (5HT) transporters are important components of its pharmacological activity, the focus was on nonselective inhibitors of monoamine transport. To reduce or eliminate the abuse potential of a DA reuptake blocker, the compounds were designed to be slow-onset, long-duration prodrugs whose N-demethylated metabolites would have increased activity over the parent compound with the ideal being a parent compound that has little or no activity. To achieve this, pairs of compounds with different groups on the amine nitrogen and with and without an additional N-methyl group were synthesized. All of the synthesized compounds were screened for binding and reuptake at the cloned human DA, 5HT, and norepinephrine (NE) transporters. As previously found, trans isomers are nonselective blockers of DA, 5HT, and NE reuptake, cis isomers with small N-alkyl groups are selective blockers of 5HT reuptake, and tertiary amines of the trans compounds are less potent than the corresponding N-demethylated secondary amines as blockers of DA reuptake. Larger N-alkyl groups in both the trans and cis series were found to reduce activity for the 5HT and NE transporters with less effect at DA transporters. Selected trans compounds were also screened for locomotor activity in mice and generalization to a cocaine-like profile in rats. With intraperitoneal administration, all of the trans isomers showed a slow onset of at least 20 min and an extremely long duration of action in the locomotor assays. Several of the trans compounds also fully generalized to a cocainelike pharmacological profile. An initial lead compound, the N,N-dimethyl analogue trans-1b, was resolved into chirally pure enantiomers. Surprisingly, both enantiomers were found to have significant affinity for the DA transporter and to cause locomotor activation. This is in contrast to the N-methyl compound in which only the (+)-enantiomer had significant activity. The absolute configuration of the more active enantiomer was determined by X-ray crystallography to be 3R,1S.

Copper(II) complexation by a series of ligands containing two 1,4,7-triazacyclononane, [9]aneN(3), groups conjoined by polymethylene chains two to six carbons in length is described. Equilibrium modeling studies in aqueous solution using pH-potentiometry indicate that the smallest homologue of the series, EM2, forms only Cu(EM2)(2+) in dilute aqueous solutions. All other ligands of the series form stable 1:1 (protonated and nonprotonated) and 2:1 dicopper(II) (hydroxo and non-hydroxo) complexes. Those ligands that contain bridging chains of four or more carbon atoms likely form dimeric or oligomeric complex species in solution. The EM ligands with the shortest polymethylene bridging groups form the most stable 1:1 species. There is little difference among the ligands (n = 3-6) in complex stability of the protonated, CuH(2)(EMn)(4+), and dicopper(II), Cu(2)(EMn)(4+), species. UV-vis spectroscopic continuous variation studies at pH 4.0 and 7.5 are interpreted on the basis of the principal equilibrium species obtained from the equilibrium models. Single-crystal X-ray diffraction studies on four complexes ([Cu(EM2)]SO(4).6H(2)O (1), [Cu(2)(EM2)Cl(4)].2H(2)O (2), [Cu(2)(EM6)Cl(4) ] (3), and [Cu(EM3)][ZnBr(4)].H(2)O (4)) characterize structural features of several 1:1 monomeric and dicopper(II) complexes in the crystalline solid. The monomeric compounds contain CuN(6) chromophores while the dicopper(II) compounds contain square pyramidal CuN(3)Cl(2) coordination geometry. Compound 1 crystallizes in space group P&onemacr; with a = 7.849(2) Å, b = 9.783(2) Å, c = 16.919(5) Å, alpha = 78.42(3) degrees, beta = 85.76(3) degrees, gamma = 73.06(3) degrees, and Z = 2. 2: P2(1)/n with a = 9.689(3) Å, b = 11.733(3) Å, c = 10.124(3) Å, beta = 98.20(2) degrees, and Z = 2. 3: P2(1)/n with a = 7.278(2) Å, b = 12.416(3) Å, c = 13.781(2) Å, beta = 90.15(2) degrees, and Z = 2. 4: P2(1)/c with a = 9.295(3) Å, b = 16.233(4) Å, c = 16.544(5) Å, beta = 92.62(2) degrees, and Z = 4. Cyclic voltammograms of aqueous solutions prepared by dissolving [Cu(2)(EM2)Cl(4)].2H(2)O confirm its dissociation to Cu(EM2)(2+). Aqueous solutions containing 1:1 molar ratios of Cu(II) and EM2 in 0.1 mol dm(-)(3) KCl at 25 degrees C show a one-electron chemically reversible reduction at scan rates of 500 mV s(-)(1) with E(1/2) (Cu(II)-Cu(I)) = -868 mV relative to SCE. EPR (X- and Q- band) spectra of frozen solutions (1:1 DMSO/H(2)O and glycerol/H(2)O) of Cu(EM2)(2+) at 100 K are typical of axial copper(II) features (X-band parameters: g( parallel) =2.225 (A( parallel) = 164 x 10(-)(4)) and g( perpendicular) = 2.045).

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The macrocyclic lactone brefeldin A was used as a test molecule for the MM3‐92 Stochastic Search conformational searching algorithm. A number of low energy conformers were found and 12 of these were also subjected to ab initio energy minimization using the 3–21G* and 6–31G* basis sets with the Spartan 5.0 package. There was reasonable agreement between the MM3‐92 and ab initio results in that almost all of the conformers found by the former were also stable low energy conformers with the latter. The structure of breflate, an ester analog of brefeldin, was also determined by X‐ray crystallography. There was very good agreement between experimental structures for the compound and the lowest energy conformer determined by the ab initio methods. This was also among the lowest conformers found by MM3‐92. Despite some imperfections in the MM3‐92 force field, the Stochastic Search method was a powerful method for determining molecular conformation. Copyright © 1999 John Wiley & Sons, Ltd.