Restrained Analogs

Enkephalins with Tyr1 restrained within the skeleton of a benzomorphan have been reported by two groups. Ramakrishnan and Portoghese 171) prepared antipodal forms of the regioisomeric derivatives 19a and 19b by routes based on corresponding 1- and 3-cyanides. All compounds 

The fact that N-arginyl-Met-enkephalin(/3-lipotropin 60-65) has an activity comparable with that of the parent by in vitro tests, 173) prompted the examination of benzomorphan derivatives in which the piperidino nitrogen was linked to a variety of amino acids (Gly, Met, Leu, Arg). The Arg derivative 20 was close in potency to Met-enkephalin in a binding assay against [3H]naloxone (as was the nor-base) and all others had very low activities.074 Peptidase action, liberating the active drug from Arg derivatives of both the enkephalin and benzomorphan, may explain these results, although there is contrary evidence in the case of peptide. 

Restraint by cyclization has also been applied to enkephalins. Cyclo-Leu5-enkephalin itself with Tyr1-NH2 joined to Leu5-C02H has been reported but 

DiMaio prepared some cyclic analogs in which Tyr-NH2 was linked to Gly2-NH by bimethylene (to form a 2-oxo-piperazine ring).(182) The compound 23 (D-configuration at C-3) was active in mice at a dose level of 50 pg in the hot-plate test and was blocked by naloxone, whereas the corresponding L(C-3) diastereoisomer was inactive. However, the compound failed to displace [3H]naloxone in a binding assay and showed no GPI activity. 

Aminoindane and related ring systems have also been employed as conformational restraints of enkephalins. The analog 24 in which 1-aminoindane replaces residues 4 and 5 of the pentapeptide retains half the GPI activity of DADL,(45) while the peptide 25 modified at the Tyr residue exceeds Leu-enkephalin in potency seven to eight times, but is 30 times less effective at MVD sites.(183) The last derivative showed no activity in mice, using the 

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Frovatnptan (6, SB-209509/VML-251), initially discovered by SmithKline Beecham, was licensed to Vanguard Medica/Vemalis for development. The marketing rights for frovatriptan have subsequently been licensed to Elan in the United States. Frovatriptan is a conformationally-restrained analog of the selective 5-HTi agonist 5-carbamoyltryptamine (5-CT). The key step in the syntheses involve Fischer reaction of 4-cyanophenylhydrazine (70) or 4-carboxamidophenylhydrazine (79) with an... 

Friedman, E., Meller, E. and Hallock, M. (1981) Effects of conformationally restrained analogs of serotonin on its uptake and binding in rat brain. J. Neurochem. 36 931-937. 

The intramolecular hydroarylaion and hydroalkenylation methodology has provided novel routes to the core unit of the quinolizidine-based homopnmiliotoxin alkaloids (Scheme 40) and the conformationally restrained analogs of the combined thromboxane antagonist/synthase inhibitor GR85305f (Scheme 41). 

For a clamped plate edge, the principal support mechanism is a boxy mass that restrains rotation about the edge of the plate (w,j( = 0) and motion transverse to the plate surface (w = 0). The four ways of supporting the boxy mass are analogous to the four ways for a simply supported edge and are shown in Appendix D. 

Biomimetic analogs with conformational restrained iron(III) complexes represent the... 

Analogous to the spherical filler of radius R in the Kraus model, Bhattacharya and Bhowmick [31] consider an elliptical filler represented by R(1 + e cos 0), in the polar coordinate. The swelling is completely restricted at the surface and the restriction diminishes radially outwards (Fig. 40 where, qt and q, are the tangential and the radial components of the linear expansion coefficient, q0). This restriction is experienced till the hypothetical sphere of influence of the restraining filler is existent. One can designate rapp [> R( 1 + e cos 0)] as a certain distance away from the center of the particle where the restriction is still being felt. As the distance approaches infinity, the swelling assumes normality, as in a gum compound. This distance, rapp, however, is not a fixed or well-defined point in space and in fact is variable and is conceived to extend to the outer surface of the hypothetical sphere of influence. 

Owing to the lack of an effective preparation method, the development of porphyrinato rare earth complexes were relatively restrained in comparison with their phthalocyaninato rare earth analogs. The first sandwich type bis(porphyrinato) rare earth complex was reported in 1983... 

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