摘要:

AbstractThe role exercised by the central residue of the chemotacticN‐formyltripeptide HCO‐Met‐Leu‐Phe‐OMe (fMLP‐OMe) in controlling both the backbone conformation and the biochemical activity is the subject of recent interest. Here, two new centrally constrained fMLP‐OMe analogues, namely HCO‐Met‐azaPro‐Phe‐OMe (4) and HCO‐Met‐(γ‐lactam)‐Phe‐OMe (6) have been synthesized and their CDCl3solution conformation and activity have been studied. The azapeptide4adopts β‐folded conformation with the azaPro residue at the i+2 position and an intramolecular H‐bond involving the formylic oxygen and the Phe NH. The γ‐lactam tripeptide6prefers a semi‐extended backbone conformation. When tested on human neutrophils both the new models were found practically devoid of biological activity. The role exerted by the NH groups as well as by t

ISSN:0365-6233    

DOI:10.1002/ardp.19963291202

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractThe dissociation equilibrium constants (Kdvalues) of dequalinium (2) and the monoquinolinium compounds1aand1bhave been determined from competition equilibrium radioligand binding with [125I]apamin on rat brain synaptic plasma membranes (SPMs). Dequalinium binds to the channel with 2 orders of magnitude higher affinity than1aor1b, suggesting that both quinolinium groups are needed for potent and selective SKCachannel blockade. The trisquinolinium compound3(1,1′‐[5‐[4‐(4‐aminoquinolinium‐1‐yl)but‐1‐yl] non‐4‐en‐1,9‐diyl]‐bis‐(4‐aminoquinolinium)) has been synthesized and tested for inhibition of the afterhyperpolarization of rat sympathetic neurones and on the binding assay. Compound3shows approximately one order of magnitude higher potency than2, being the most potent non‐peptidic SKCachannel blocker reported so far (Kd∽ 30 nM). The higher affinity of3compared with2may be due to direct binding of the third quinolinium group to the channel or may arise from a reduction of the unfavorable entropy of binding via an increase of the „local

ISSN:0365-6233    

DOI:10.1002/ardp.19963291203

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractSome 2‐arylpyrazolo[1,5‐c][1,3]benzoxazin‐5‐ones1and 5‐oxopyrazolo[1,5‐c][1,3]benzoxazin‐2‐carboxylates2were prepared and biologically evaluated for their binding at benzodiazepine receptor (BZR) in rat cortical membranes. Structure‐activity relationship studies suggest that, although proton donor d and proton acceptor a1are both optional pharmacophoric descriptors, at least one of them must be present for good BZR affinity. When the proton donor d is not present, the heteroatom acceptor a1is necessary either in the tricyclic core or in the appended substituent at the C‐2 to obtain sub‐mi

ISSN:0365-6233    

DOI:10.1002/ardp.19963291204

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractNineteen 4‐substituted 1,2,4‐oxadiazol‐5‐ones (6a‐s) were prepared as prodrugs for lipophilic hydroxyguanidines which should be metabolizedin vivoto nitric oxide. This hypothesis was tested indirectly by measuring the antithrombotic properties of these compounds 2 h after oral administration to rats (60 mg/kg). In mesenteric arterioles seven compounds moderately (≥ 10%) inhibited the formation of thrombi by a laser beam. Maximum effects were observed in6c(4‐pentyl) and6f(4‐benzyl). The lack of activity in the corresponding 2‐pentyloxadiazolone10c, where no formation of nitric oxide seems possible, indirectly suggests that the antithrombotic properties of the title compounds could be mediated by thein vivoformatio

ISSN:0365-6233    

DOI:10.1002/ardp.19963291205

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractHydroxyindolones (1–6, 15–16) were transformed into isatinylidenes (7,9–13, 17–19) by dehydration with 4‐toluenesulfonic acid. The dimer‐type compounds (14, 20) were also isolated in a few cases. The obtained isatinylidenes were transformed into 3‐spiro‐cyclopropane‐oxindoles (21–32) with dimethyloxosulfonium methylide. Compound22shows protective effects against hypobaric hypoxia and triethyltin

ISSN:0365-6233    

DOI:10.1002/ardp.19963291206

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

AbstractReactions of 5‐carboxamido‐5H‐dibenz[b,f]azepines (1a–1d) with glyoxylic acid methylester methyl hemiacetal (GMHA) led to 5‐(carboxamido‐N‐α‐hydroxy‐acetic acid methyl ester)‐5H‐dibenz[b,f]azepines (2a–2d). The reactions with glycols yielded the oligoethylene glycol derivatives (3,4). The new compounds were screened as anticonvulsants and

ISSN:0365-6233    

DOI:10.1002/ardp.19963291207

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

摘要:

Abstract3‐Hydroxymethylphenytoin valproic acid ester (VAL‐PHT) was designed as a new prodrug combining valproic acid and phenytoin, two anticonvulsant drugs with different pharmacological profiles. The compound was hydrolyzed by rat plasma esterasesin vitrobut exhibited only activity in the maximal electroshock seizure test (MES test) after intraperitoneal administration to mice. The compound did not protect against pentylenetetrazole‐induced seizures. It is concluded that VAL‐PHT acts as a prodrug displaying the anticonvulsant profile of ph

ISSN:0365-6233    

DOI:10.1002/ardp.19963291208

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY

ISSN:0365-6233    

DOI:10.1002/ardp.19963291201

出版商:WILEY‐VCH Verlag    

年代:1996

数据来源: WILEY