L(S)- and D(R)-3-amino-1-phenylpyrrolidines. Stereoselective antagonists for histamine and acetylcholine receptors in vitro

Witiak, Donald T.; Muhi-Eldeen, Zuhair; Mahishi, Narain; Sethi, O. P.; Gerald, Michael C.

doi:10.1021/jm00283a006

Cited by 17 publications

(18 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Clofibrate administration is associated with depressed incorporation of 14C-pyruvate or 14C-acetate into cholesterol or mevalonate by liver slices, and the observations by White indicate that this drug regulates hepatic cholesterol biosynthesis by inhibiting microsomal reduction of HMG-CoA to mevalonate (25). Inhib-itory effects in vitro on the incorporation of mevalonate-2 -14C into nonsaponifiable material in rat liver homogenate, with the corresponding carboxylic acids of a selected number of our analogs (4,5), are also in agreement with hypocholesterolemic properties observed for the esters in vivo. Esters I, V and VII return serum cholesterol levels in hyperlipemic rats back to normal in vivo; the corresponding carboxylic acids are equally effective inhibitors of cholesterol biosynthesis in vitro.…”

Section: Sc Ussl Onsupporting

confidence: 77%

See 1 more Smart Citation

Differential effects of benzodioxane, chroman and dihydrobenzofuran analogs of clofibrate in a triton hyperlipemic rat model

Newman

Hellman

Witiak

1973

Lipids

Self Cite

View full text Add to dashboard Cite

Clofibrate (ethyl 2‐methyl‐2‐[4‐chlorophenoxy] propionate) is currently an important hypolipemic agent. In this study we describe the biological properties of certain acyclic and cyclic analogs of clofibrate in a hyperlipemic rat model in which the hyperlipemia was induced by ip injection of Triton WR‐1339. Cyclic analogs studied for their hypocholesterolemic and hypotriglyceridemic activities, as well as their ability to modify lipoprotein patterns, include the ethyl esters of 1,4‐benzodioxane‐2‐carboxylic acid, 6‐chlorochroman‐2‐carboxylic acid and 5‐chloro‐2,3‐dihydrobenzofuran‐2‐carboxylic acid. Among the clofibrate analogs, ethyl 6‐chlorochroman‐2‐carboxylate compares most favorably with the parent compound. Whereas the 6‐chlorochroman‐2‐carboxylate is effective as a hypocholesterolemic and hypotriglyceridemic agent, the 1,4‐benzodioxane analog exhibits mainly hypotriglyceridemic activity, while the 2,3‐dihydrobenzofuran analog exhibits hypocholesterolemic activity. Except for the benzodioxane, deschloro analogs are inactive. Results obtained in these studies are discussed in terms of structural requirements for biological activity and modes of action proposed for the parent drug clofibrate.

show abstract

Section: Sc Ussl Onsupporting

confidence: 77%

“…Analogs I-VIII were synthesized according to methods previously reported by Witiak and coworkers (2)(3)(4)(5). These compounds were tested in a hyperlipemic rat model (11) in which the hyperlipemia was induced by ip injection of Triton WR-1339 (oxyethylated tertiaryoctylphenolformaldehyde polymer, Ruger Chemical Co., Philadelphia, Pa.).…”

Section: Methodsmentioning

confidence: 99%

Differential effects of benzodioxane, chroman and dihydrobenzofuran analogs of clofibrate in a triton hyperlipemic rat model

Newman

Hellman

Witiak

1973

Lipids

Self Cite

View full text Add to dashboard Cite

show abstract

“…4c), the different activities of the two isomers can be explained by stating that maximum antihistaminic activity is associated with a N-centroid distance not shorter than 6.0/L It should be noted, however, that other important factors contribute to the antihistaminic activity of a given compound, in particular its pK a value (Barlow, 1968), its lipophilicity and the presence or absence of another unsaturated ring in the molecule. As regards, in particular, this latter factor, all the experimental data agree in indicating that the presence of two unsaturated rings produces compounds which are most potent as antihistamines (Witiak, Muhi-Eldeen, Mahishi, Sethi & Gerald, 1971;Ariens, 1977) and, moreover, the different activities observed for the two enantiomers of chiral antihistamines seem to imply the need for at least three sites, most probably the amino N and the two unsaturated rings, in the drug-receptor interaction (Witiak et al, 1971).…”

Section: O(2a)-h(2a)o(4a) 172mentioning

confidence: 63%

Crystallographic and conformational studies on histamine H₁ receptor antagonists. I. Structure of carbinoxamine maleate

Bertolasi¹,

Pa²,

Gilli³

et al. 1980

Acta Crystallogr Sect B

View full text Add to dashboard Cite

Carbinoxamine maleate, CI6H20CIN20 +. C4H304, crystallizes in space group P21212~ with a = 10.527 (3), b = 11.151 (3), c = 17.626 (4) A andZ= 4. Diffractometer data were collected with Cu Kct radiation and the structure was refined to an R value of 0.045 using 1448 observed reflections. The compound crystallizes with spontaneous resolution of the enantiomers and the absolute configuration of carbinoxamine was determined to be S in the crystal under investigation. The crystal is built by ion pairs linked by an intermolecular hydrogen bond. The five-membered aminoethyl chain assumes a conformation such as to reproduce the distance between the amino N and the centroid of an aromatic ring already observed in other antihistamines with different chains. Conformational-energy calculations suggest that the conformation found in the crystal corresponds to a minimum for the free ion.

show abstract

“…The solution was stirred for 6 h at 60°C. The acetic anhydride was removed in vacuo and consecutive washes with toluene (2 × 10 mL) and hexanes (2 × 10 mL) followed, leaving N-tBoc-L-aspartic anhydride as previously described (29). The crude white solid was used without further purification for nucleophilic addition to the anhydride, similar to the method previously reported (30).…”

Section: Methodsmentioning

confidence: 99%

The central cavity in trimeric glutamate transporters restricts ligand diffusion

Leary¹,

Holley²,

Stone

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

A prominent aqueous cavity is formed by the junction of three identical subunits in the excitatory amino acid transporter (EAAT) family. To investigate the effect of this structure on the interaction of ligands with the transporter, we recorded currents in voltageclamped Xenopus oocytes expressing EAATs and used concentration jumps to measure binding and unbinding rates of a highaffinity aspartate analog that competitively blocks transport (β-2-fluorenyl-aspartylamide; 2-FAA). The binding rates of the blocker were approximately one order of magnitude slower than L-Glu and were not significantly different for EAAT1, EAAT2, or EAAT3, but 2-FAA exhibited higher affinity for the neuronal transporter EAAT3 as a result of a slower dissociation rate. Unexpectedly, the rate of recovery from block was increased by L-Glu in a saturable and concentration-dependent manner, ruling out a firstorder mechanism and suggesting that following unbinding, there is a significant probability of ligand rebinding to the same or neighboring subunits within a trimer. Consistent with such a mechanism, coexpression of wild-type subunits with mutant (R447C) subunits that do not bind glutamate or 2-FAA also increased the unblocking rate. The data suggest that electrostatic and steric factors result in an effective dissociation rate that is approximately sevenfold slower than the microscopic subunit unbinding rate. The quaternary structure, which has been conserved through evolution, is expected to increase the transporters' capture efficiency by increasing the probability that following unbinding, a ligand will rebind as opposed to being lost to diffusion.synaptic transmission | membrane transport M embers of the SLC1 solute carrier family include transporters for acidic (EAAT1-5; SLC1A1-3, 6, 7) and neutral (ASCT1, 2; SLC1A4, 5) amino acids in mammals. Recent phylogenetic studies indicate the existence of at least two additional members of this gene family (SLC1A8, 9) that were lost in the lineage leading to mammals (1). The mammalian excitatory amino acid transporters (EAAT1-5) are secondary active transporters that help terminate glutamatergic synaptic transmission within the central nervous system by removing transmitter (L-Glu) from the extracellular space (2). EAATs can maintain an intracellular-to-extracellular L-Glu concentration ratio exceeding 10 6 by stoichiometrically coupling L-Glu transport to cotransport of 3 Na + , 1 H + , and 1 L-Glu and countertransport of 1 K + (3, 4). The crystal structure of the outward-facing state of the archaeal glutamate transporter homolog Glt Ph features a prominent aqueous cavity framed by three subunits forming a homotrimer (5, 6). One aspartate/glutamate binding site in each subunit faces the aqueous cavity near its base, approximately halfway across the plane of the lipid bilayer. Functional and biochemical studies of homologous mammalian glutamate transporters are consistent with this trimeric structure and indicate that each subunit functions as an independent transporter (7-9). The recent str...

show abstract

L(S)- and D(R)-3-amino-1-phenylpyrrolidines. Stereoselective antagonists for histamine and acetylcholine receptors in vitro

Cited by 17 publications

References 2 publications

Differential effects of benzodioxane, chroman and dihydrobenzofuran analogs of clofibrate in a triton hyperlipemic rat model

Differential effects of benzodioxane, chroman and dihydrobenzofuran analogs of clofibrate in a triton hyperlipemic rat model

Crystallographic and conformational studies on histamine H₁ receptor antagonists. I. Structure of carbinoxamine maleate

The central cavity in trimeric glutamate transporters restricts ligand diffusion

Contact Info

Product

Resources

About

L(S)- and D(R)-3-amino-1-phenylpyrrolidines. Stereoselective antagonists for histamine and acetylcholine receptors in vitro

Cited by 17 publications

References 2 publications

Differential effects of benzodioxane, chroman and dihydrobenzofuran analogs of clofibrate in a triton hyperlipemic rat model

Differential effects of benzodioxane, chroman and dihydrobenzofuran analogs of clofibrate in a triton hyperlipemic rat model

Crystallographic and conformational studies on histamine H1 receptor antagonists. I. Structure of carbinoxamine maleate

The central cavity in trimeric glutamate transporters restricts ligand diffusion

Contact Info

Product

Resources

About

Crystallographic and conformational studies on histamine H₁ receptor antagonists. I. Structure of carbinoxamine maleate