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1.
J Org Chem ; 85(12): 8013-8020, 2020 Jun 19.
Article in English | MEDLINE | ID: mdl-32469215

ABSTRACT

We probed tandem aldol condensations of sixteen o-hydroxyacetophenones, carrying electron-withdrawing and -donating groups at positions 4 and 5, using five molar equivalents of SiCl4 in anhydrous ethanol. Substrates carrying electron-withdrawing groups (EWGs) (0 < ∑σ > 0.63) populated the equilibria with isospiropyrans (12-74% yield), while those carrying electron-donating groups (EDGs) (∑σ < -0.31) gave flavylium salts (50-80%) or thermochromic bis-spiropyrans (73%). The results are of interest for developing novel organic materials possessing switchable photochromic and thermochromic characteristics.

2.
Eur Neuropsychopharmacol ; 25(9): 1448-61, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25583363

ABSTRACT

The D3 dopamine receptor represents an important target in drug addiction in that reducing receptor activity may attenuate the self-administration of drugs and/or disrupt drug or cue-induced relapse. Medicinal chemistry efforts have led to the development of D3 preferring antagonists and partial agonists that are >100-fold selective vs. the closely related D2 receptor, as best exemplified by extended-length 4-phenylpiperazine derivatives. Based on the D3 receptor crystal structure, these molecules are known to dock to two sites on the receptor where the 4-phenylpiperazine moiety binds to the orthosteric site and an extended aryl amide moiety docks to a secondary binding pocket. The bivalent nature of the receptor binding of these compounds is believed to contribute to their D3 selectivity. In this study, we examined if such compounds might also be "bitopic" such that their aryl amide moieties act as allosteric modulators to further enhance the affinities of the full-length molecules for the receptor. First, we deconstructed several extended-length D3-selective ligands into fragments, termed "synthons", representing either orthosteric or secondary aryl amide pharmacophores and investigated their effects on D3 receptor binding and function. The orthosteric synthons were found to inhibit radioligand binding and to antagonize dopamine activation of the D3 receptor, albeit with lower affinities than the full-length compounds. Notably, the aryl amide-based synthons had no effect on the affinities or potencies of the orthosteric synthons, nor did they have any effect on receptor activation by dopamine. Additionally, pharmacological investigation of the full-length D3-selective antagonists revealed that these compounds interacted with the D3 receptor in a purely competitive manner. Our data further support that the 4-phenylpiperazine D3-selective antagonists are bivalent and that their enhanced affinity for the D3 receptor is due to binding at both the orthosteric site as well as a secondary binding pocket. Importantly, however, their interactions at the secondary site do not allosterically modulate their binding to the orthosteric site.


Subject(s)
Dopamine Antagonists/metabolism , Dopamine Antagonists/pharmacology , Receptors, Dopamine D3/antagonists & inhibitors , Allosteric Regulation , Animals , Arrestins/metabolism , Binding, Competitive , CHO Cells , Cricetulus , Dopamine Antagonists/chemistry , Drug Evaluation, Preclinical , Humans , Molecular Structure , Radioligand Assay , Receptors, Dopamine D3/genetics , Receptors, Dopamine D3/metabolism , beta-Arrestins
3.
Inorg Chem ; 49(12): 5413-23, 2010 Jun 21.
Article in English | MEDLINE | ID: mdl-20481630

ABSTRACT

The anhydrides of [hydroxy(methanesulfonato-O)]iodobenzene (HMIB) and [hydroxy(toluenesulfonato-O)]iodobenzene (HTIB) were prepared by drying acetonitrile solutions of the compounds. The anhydrides of the hypothetical compounds [hydroxy(chloroacetato)-O]iodobenzene and [hydroxy(iodoacetato)-O]iodobenzene were obtained from aqueous solutions. Crystallographic structures were obtained for the anhydrides, except that of HTIB. The electron-domain geometries of the I atoms vis-a-vis secondary I...O bonds were explored. The presence of delocalized bonding in groupings of O and I atoms was suggested. A linear relationship between the C-I-O angles and the I-O bond orders was observed.


Subject(s)
Anhydrides/chemical synthesis , Iodobenzenes/chemical synthesis , Anhydrides/chemistry , Iodobenzenes/chemistry , Models, Molecular , Molecular Structure
4.
Behav Pharmacol ; 21(3): 171-81, 2010 May.
Article in English | MEDLINE | ID: mdl-20463460

ABSTRACT

Dopaminergic (DA) agonist-induced yawning in rats seems to be mediated by DA D3 receptors, and low doses of several DA agonists decrease locomotor activity, an effect attributed to presynaptic D2 receptors. Effects of several DA agonists on yawning and locomotor activity were examined in rats and mice. Yawning was reliably produced in rats, and by the cholinergic agonist, physostigmine, in both the species. However, DA agonists were ineffective in producing yawning in Swiss-Webster or DA D2R and DA D3R knockout or wild-type mice. The drugs significantly decreased locomotor activity in rats at one or two low doses, with activity returning to control levels at higher doses. In mice, the drugs decreased locomotion across a 1000-10 000-fold range of doses, with activity at control levels (U-91356A) or above control levels [(+/-)-7-hydroxy-2-dipropylaminotetralin HBr, quinpirole] at the highest doses. Low doses of agonists decreased locomotion in all mice except the DA D2R knockout mice, but were not antagonized by DA D2R or D3R antagonists (L-741 626, BP 897, or PG01037). Yawning does not provide a selective in-vivo indicator of DA D3R agonist activity in mice. Decreases in mouse locomotor activity by the DA agonists seem to be mediated by D2 DA receptors.


Subject(s)
Dopamine Agonists/pharmacology , Motor Activity/drug effects , Yawning/drug effects , Analysis of Variance , Animals , Cholinesterase Inhibitors/pharmacology , Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Dose-Response Relationship, Drug , Drug Interactions , Mice , Mice, Inbred C3H , Mice, Knockout , Motor Activity/genetics , Physostigmine/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D2/deficiency , Yawning/genetics
5.
J Med Chem ; 51(19): 6095-109, 2008 Oct 09.
Article in English | MEDLINE | ID: mdl-18774793

ABSTRACT

Discovering dopamine D2-like receptor subtype-selective ligands has been a focus of significant investigation. The D2R-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole (1, L741,626; K(i)(D2R/D3R) = 11.2:163 nM) has previously provided a lead template for chemical modification. Herein, analogues have been synthesized where the piperidine was replaced by a tropane ring that reversed the selectivity seen in the parent compound, in human hD2(L)R- or hD3R-transfected HEK 293 cells (31, K(i)(D2R/D3R) = 33.4:15.5 nM). Further exploration of both N-substituted and aryl ring-substituted analogues resulted in the discovery of several high affinity D2R/D3R ligands with 3-benzofurylmethyl-substituents (e.g., 45, K(i)(D2R/D3R) = 1.7:0.34 nM) that induced high affinity not achieved in similarly N-substituted piperidine analogues and significantly (470-fold) improved D3R binding affinity compared to the parent ligand 1. X-ray crystallographic data revealed a distinctive spatial arrangement of pharmacophoric elements in the piperidinol vs tropine analogues, providing clues for the diversity in SAR at the D2 and D3 receptor subtypes.


Subject(s)
Azabicyclo Compounds/pharmacology , Receptors, Dopamine D2/drug effects , Azabicyclo Compounds/chemical synthesis , Azabicyclo Compounds/chemistry , Binding Sites , Crystallography, X-Ray , Ligands , Models, Molecular , Molecular Structure , Receptors, Dopamine D2/chemistry , Stereoisomerism , Structure-Activity Relationship
6.
J Org Chem ; 71(24): 9035-44, 2006 Nov 24.
Article in English | MEDLINE | ID: mdl-17109527

ABSTRACT

The synthesis and conformational properties of folded dendrons based on a 2-methoxyisophthalamide (2-OMe-IPA) repeat unit are described. The hydrodynamic properties of dendrons preorganized via the syn-syn conformational preference of 2-methoxyisophthalamide are compared with 2,6-pyridinedicarboxamide (2,6-pydic) analogues. The effect of subtle differences in the nature of the conformational equilibria that exist within the 2-OMe-IPA and 2,6-pydic repeat units on the global structural properties of the corresponding dendrons was explored computationally, by (1)H-DOSY NMR spectroscopy and time-resolved fluorescence anisotropy (TRFA) measurements. Whereas the syn-syn preference of the 2-OMe-IPA branched repeat unit is stabilized entirely by intramolecular hydrogen-bonding interactions, this preference in the 2,6-pydic system is a consequence of both intramolecular hydrogen-bonding and dipole minimization effects. However, nonspecific solvophobic compression is more important in determining hydrodynamic properties than solvent-dependent shifts in the conformational equilibria of the repeat unit for both dendron series.


Subject(s)
Amides/chemistry , Dendrimers/chemistry , Phthalic Acids/chemistry , Crystallography, X-Ray , Fluorescence Polarization , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure
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