Stereochemical dependence of pharmacological activity in a series of optically active N-methylated barbiturates

Büch, H.; Schneider-Affeld, F.; Rummel, W.; Knabe, J.

doi:10.1007/bf00501159

Cited by 58 publications

(9 citation statements)

References 8 publications

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“…9 Thus, for methyl phenobarbital and hexobarbital, the S -(+)-isomers induced sleep and R -(−)-enantiomer was ineffective. In contrast, the R -(−)-isomers of 5- ethyl -5-cyclohexenyl barbiturate and mephobarbital were hypnotic agents, and the S -(+)-isomers had no activity.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the R -(−)-isomers of 5- ethyl -5-cyclohexenyl barbiturate and mephobarbital were hypnotic agents, and the S -(+)-isomers had no activity. 9,56 Further extension of the carbon-5 noncyclic substituent (i.e. from ethyl to propyl) did not change the relative enantiomer potency ( R was still more potent than S ), and the R -(−)-isomer was still an anesthetic, however the S -(+)-isomer was a convulsant.…”

Section: Discussionmentioning

confidence: 99%

“…mephobarbital, hexobarbital), on the exocyclic 5-substituent (pentobarbital, thiopental), or both (methohexital). 46 In general, stereoisomers generated by either of these chiral centers displayed rather small differences in biological activities, 9,47–54 although the precise assessment of this effect is difficult due to the different rates of the stereoisomer metabolism and differential binding by serum albumin. 53 Hence, despite the plethora of available biological results, it is difficult to compare literature data on barbiturate potency and efficacy with those of the enantiomers of the compound 14 presented here.…”

Section: Discussionmentioning

confidence: 99%

“…For example, adding a single methyl group to the general anesthetic pentobarbital (5-ethyl-5-( pentan-2-yl )pyrimidine-2,4,6(1H,3H,5H)-trione) produces the convulsant DMBB (5-ethyl-5-( 4-methylpentan-2-yl )pyrimidine-2,4,6(1H,3H,5H)-trione). 7–9 Such sensitivity to small changes in barbiturate chemical structure implies there are specific barbiturate binding sites as evidenced by saturable and stereospecific binding of radiolabeled pentobarbital to nACh receptor. 10 …”

Section: Introductionmentioning

confidence: 99%

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Allyl m-Trifluoromethyldiazirine Mephobarbital: An Unusually Potent Enantioselective and Photoreactive Barbiturate General Anesthetic

et al. 2012

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We synthesized 5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid (14), a trifluoromethyldiazirine-containing derivative of general anesthetic mephobarbital, separated the racemic mixture into enantiomers by chiral chromatography, and determined the configuration of the (+)-enantiomer as S by x-ray crystallography. Additionally, we obtained the 3H-labeled ligand with high specific radioactivity. R-(−)-14 is an order of magnitude more potent than the most potent clinically used barbiturate, thiopental, and its general anesthetic EC50 approaches those for propofol and etomidate, whereas S-(+)-14 is tenfold less potent. Furthermore, at concentrations close to its anesthetic potency, R-(−)-14 both potentiated GABA-induced currents and increased the affinity for the agonist muscimol in human α1β2/3γ2L GABAA receptors. Finally, R-(−)-14 was found to be an exceptionally efficient photolabeling reagent, incorporating into both α1 and β3 subunits of human α1β3 GABAA receptors. These results indicate R-(−)-14 is a functional general anesthetic that is well-suited for identifying barbiturate binding sites on Cys-loop receptors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Allyl m-Trifluoromethyldiazirine Mephobarbital: An Unusually Potent Enantioselective and Photoreactive Barbiturate General Anesthetic

et al. 2012

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“…In the process of identifying novel anesthetics, comparison of the actions of geometric isomers of certain volatile fluorinated ethers and barbiturate stereoisomers sometimes revealed that one isomer acted as an anesthetic and the other as a convulsant (2)(3)(4)(5). Anesthetic barbiturates and other intravenous anesthetics (propofol, etomidate, and steroids), as well as volatile ethers, potentiate inhibitory GABA type A receptors (GABA A R) 2 in vitro at concentrations producing anesthesia in vivo (6 -8), and the importance of GABA A Rs for anesthesia is demonstrated by the decreased sensitivity of "knock-in" mice bearing a single amino acid substitution in a GABA A R ␤ subunit to the immobilizing and hypnotic effects of pentobarbital, etomidate, and propofol (9 -12).…”

mentioning

confidence: 99%

Positive and Negative Allosteric Modulation of an α1β3γ2 γ-Aminobutyric Acid Type A (GABAA) Receptor by Binding to a Site in the Transmembrane Domain at the γ+-β− Interface

Jayakar

Zhou

Savechenkov

et al. 2015

Journal of Biological Chemistry

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Background: For some chiral barbiturates, one isomer potentiates and the other inhibits GABA responses by binding to unknown sites. Results: A photoreactive convulsant barbiturate identifies a transmembrane intersubunit-binding site between the ␥ and ␤ subunits. Conclusion: Positive and negative allosteric modulators can bind to a common intersubunit site. Significance: This study defines a novel mode of regulation of GABA A R responses.

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Barbitursäurederivate, 19. Mitt. 5‐Äthyl‐5‐propyl‐1N‐methylbarbitursäure

Knabe¹,

Franz²

1975

Archiv der Pharmazie

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d1fferent1at10n 0f m0u5e erythr01eukem1a (MEL) ce115 1ead5 t0 c0mp1ex chan9e5 1n c-myc mRNA 1eve15. W1th1n 1-2 hr after the add1t10n 0f the 1nducer hexamethy1ene 615acetam1de (HM8A), c-myc mRNA 1eve15 decrea5e 10-t0 20-f01d and rema1n 10w unt11 12-24 hr, at wh1ch t1me the mRNA reaccumu1ate5 t0 1t5 0r191na1 1eve1. 7hereafter a5 the ce115 under90 term1na1 d1fferent1at10n, c-myc mRNA a9a1n dec11ne5 t0 a 10w 1eve1. We have 1nve5t19ated the re9u1at10n 0f the5e chan9e5 6y mea5ur1n9 c-myc 9ene tran5cr1pt10n and mRNA turn0ver. We f1nd that the ear1y rap1d dec11ne 1n c-myc mRNA 15 due t0 an 1ncrea5e 1n the 610ck t0 e10n9at10n 0f tran5cr1pt10n w1th1n the c-myc f1r5t ex0n. Effect1ve c-myc tran5cr1pt10n 15 then re5t0red after 2 hr 0f HM8A treatment t0 the 1eve1 pre5ent 1n un1nduced ce115 and 15 ma1nta1ned thr0u9h0ut the rema1nder 0f the d1fferent1at10n pr09ram. 7he5e re5u1t5 dem0n5trate that, except f0r the rap1d dec11ne 1n c-myc mRNA 1mmed1ate1y f0110w1n9 1nducer treatment, a11 5u65e4uent re9u1at10n 0f me55a9e 1eve15 0ccur5 thr0u9h p05t-tran5cr1pt10na1 mechan15m5.5tud1e5 0f c-myc mRNA turn0ver 5u99e5t that 50me p05t-tran5cr1pt10na1 re9u1at10n 15 nuc1ear. [Key W0rd5: M0u5e erythr01eukem1a ce115; c-myc RNA 1eve15; tran5cr1pt10na1 mechan15m5] Rece1ved Ju1y 2, 1987; rev15ed ver510n accepted 5eptem6er 18, 1987. MEL ce115 are erythr01d precur50r ce115 that are 610cked at an ear1y 5ta9e 0f erythr01d d1fferent1at10n [Mark5 and R1fk1nd 1978}. Up0n treatment w1th 0ne 0f a var1ety 0f chem1ca1 1nduc1n9 a9ent5 5uch a5 d1methy15u1f0x1de (DM50) 0r hexamethy1ene 615acetam1de (HM8A}, MEL ce1111ne5 re1n1t1ate a pr09ram 0f erythr01d d1fferent1at10n cu1m1nat1n9 1n exten51ve hem091061n 5ynthe515 and ter-m1na1 ce11 d1v1510n {Reu6en et a1. 1976; Mark5 and R1f-k1nd 1978}. F0110w1n9 a 12 t0 18-hr 1atency per10d, there 15 an 1ncrea51n9 percenta9e 0f ce115 that are 9radua11y re-cru1ted 1nt0 a c0mm1tment pr09ram (6u5e11a et a1. 1976). 0nce c0mm1tted, ce115 are capa61e 0f term1na1 d1fferent1at10n 1n the a65ence 0f further exp05ure t0 1n-ducer. We have prev10u51y 5h0wn that the 1eve1 0f c-myc mRNA 15 dra5t1ca11y a1tered dur1n9 th15 1atent per10d {Lachman and 5k0u1tch1 1984). F1r5t, there 15 a 10-f01d decrea5e 1n c-myc mRNA5, w1th1n 1-2 hr f0110w1n9 the add1t10n 0f 1nducer5 0f d1fferent1at10n. 7he 1eve1 0f c-myc tran5cr1pt5 rema1n5 re1at1ve1y 10w unt11 12-24 hr 0f 1nducer treatment when c-myc mRNA5 reaccumu1ate tran51ent1y. 7he ear1y dec11ne 1n c-myc mRNA and 1t5 5u65e4uent reexpre5510n ju5t pr10r t0 c0mm1tment 0r191-na11y 1ed u5 t0 5u99e5t that 60th event5 are 1mp0rtant f0r term1na1 d1fferent1at10n (Lachman and 5k0u1tch1 1984). 7he effect5 0f ex09en0u5 myc 9ene5 0n MEL ce11 d1ffer-ent1at10n 5upp0rt th15 hyp0the515 (C0pp01a and C01e 1986; Dm1tr0v5ky et a1. 1986; Lachman et a1. 1986; Pr0-ch0wn1k and Kuk0w5ka 1986). 7ran5cr1pt10na1 and p05t-tran5cr1pt10na1 mechan15m5 have 60th 6een 5h0wn t0 m0du1ate c-myc mRNA 1eve15 1n a var1ety 0f 6101091ca1 5y5tem5 {f0r rev1ew, 5ee Marcu 1987). 1n 50me 51tuat10n5, 0ne type 0f mechan15m ha5 6een a5cr16ed the ma1n, 1f n0...

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Stereochemical dependence of pharmacological activity in a series of optically active N-methylated barbiturates

Cited by 58 publications

References 8 publications

Allyl m-Trifluoromethyldiazirine Mephobarbital: An Unusually Potent Enantioselective and Photoreactive Barbiturate General Anesthetic

Allyl m-Trifluoromethyldiazirine Mephobarbital: An Unusually Potent Enantioselective and Photoreactive Barbiturate General Anesthetic

Positive and Negative Allosteric Modulation of an α1β3γ2 γ-Aminobutyric Acid Type A (GABAA) Receptor by Binding to a Site in the Transmembrane Domain at the γ+-β− Interface

Barbitursäurederivate, 19. Mitt. 5‐Äthyl‐5‐propyl‐1N‐methylbarbitursäure

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