Monosubstituted Analogues Research Articles

Pharmacological characterization of VIP receptors in human lung membranes

The ability of VIP, PHI, secretin, helodermin, and seven N-terminally D-amino monosubstituted VIP and PHI analogs to occupy ( 125I)iodo-VIP labeled receptors and to activate adenylate cyclase was tested on human lung membranes purified by the method of Schachter et al. Best fitted Kd, Kact and % of max. values suggested the coexistence, in near equal proportions, of two classes of VIP-preferring binding sites coupled to adenylate cyclase that showed similar decreasing affinity for: VIP > (D-Ala 4)-VIP > (D-Asp 3)-VIP = (D-Ser 2)-VIP > (D-His 1)-VIP > PHI > (D-Phe 2)-VIP > (D-Phe 4)-VIP. (D-Arg 2)-VIP was a non-selective agonist. A third receptor type, coupled to adenylate cyclase and showing high affinity for secretin and helodermin but not for VIP, was also detected.

Separation of the enantiomers of substituted putrescine and cadaverine analogues by gas chromatography on chiral and achiral stationary phases

Capillary gas chromatography (GC) on chiral stationary phases, i.e., Chirasil-Val [ l-valine- tert.-( R)-α-butylamide] and XE-60- S-valine-( R-α-phenylethylamide, has been applied to the resolution of various substituted analogues of putrescine as their N,N′-perfluoroacyl derivatives. The influence of the nature of the substituent on the retention behaviour and on the resolution of the enantiomers was studied. The results are discussed in terms of volatility analogues with two chiral centres were also clearly resolved into their corresponding stereoisomers. When the chain length between the two amino groups was increased, no clear resolution was obtained of the monosubstituted cadaverine analogues as their N,N′-perfluoroacyl derivatives. However, resolution was obtained after derivatization of the cadaverine analogues with ( — )-α-methoxy-α-trifluoromethylphenylacetyl chloride, followed by GC analysis on an achiral phase.

Lewis-base adducts of Group 1B metal(I) compounds. Part 5. Synthesis and crystal structures of adducts of silver(I) thiocyanate with 2- and 3-methylpyridine, 2,6-dimethylpyridine, and quinoline

The crystal structures of the title compounds [{Ag(SCN)L}n][L = 2-methylpyridine (1), 3-methylpyridine (2), or 2,6-dimethylpyridine (3)] and [{Ag(SCN)L2}n][L = quinoline (4)] have been established by single-crystal X-ray diffraction methods at 295(1) K and refined by least squares to residuals of 0.061, 0.046, 0.055, and 0.031 for 1 139, 1 478, 956, and 2 399 independent ‘observed’ reflections respectively. Crystals of (1) are orthorhombic, space group Pn21a, with a= 18.350(5), b= 11.209(3), c= 4.180(1)A, and Z= 4; the structure is an infinite two-dimensional polymer parallel to bc, with silver atoms pseudo-tetrahedrally four-co-ordinated by the sulphur and nitrogen atoms of bridging thiocyanate groups [Ag–S, 2.552(3) and 2.637(3); Ag–N, 2.27(1)A] and by the 2-methylpyridine [Ag–N, 2.34(1)A]. There is some disorder. Crystals of (2) are orthorhombic, space group Pbca, with a= 18.055(8), b= 11.385(5), c= 8.404(4)A, and Z= 8. The structure is an infinite two-dimensional polymer parallel to bc with silver atoms pseudo-tetrahedrally four-co-ordinated by the sulphur and nitrogen atoms of the bridging thiocyanate groups [Ag–S, 2.578(2) and 2.615(2); Ag–N, 2.293(5)A] and by the 3-methylpyridine [Ag–N, 2.331(5)A]. Crystals of (3) are monoclinic, space group P21/c, with a= 8.481(3), b= 8.102(2), c= 13.676(7)A, β= 97.41 (3)°, and Z= 4. The structure is a one-dimensional polymer generated by the 21 screw along b; the silver atom is three-co-ordinated by sulphur and nitrogen atoms of the bridging thiocyanate ligand [Ag–S, 2.474(3); Ag–N, 2.28(1)A] and by the 2,6-dimethylpyridine ligand [Ag–N, 2.275(8)A]. The change in co-ordination number in the latter complex is attributable to the increased steric bulk of the 2,6-dimethylpyridine ligand compared to the monosubstituted analogues. Crystals of (4) are orthorhombic, space group P212121, with a= 15.977(4), b= 13.544(4), c= 8.009(2)A, and Z= 4. The structure is the first established for a silver halide/pseudo-halide–nitrogen base complex with 1 : 2 stoicheiometry. It is a one-dimensional polymer generated by the 21screw along c, with four-co-ordinate pseudo-tetrahedral silver atoms linked by S, N-bridging thiocyanate groups [Ag–S, 2.495(1); Ag–N, 2.332(5)A]. The remaining two co-ordination sites of the silver are filled by quinoline nitrogen atoms [Ag–N, 2.364(3) and 2.361 (4)A].

Somatostatin receptors on rat anterior pituitary membranes.

[125I]Iodo-Tyr1-somatostatin (SRIF) binds with high affinity to one class of sites in the rat anterior pituitary with a KD of 0.91 +/- 0.22 nM and a receptor concentration of 104.4 +/- 1.9 fmol/mg protein. This binding is saturable with respect to tissue concentration and is time-, temperature-, pH-, and calcium-dependent. It is also reversible as a function of time. The rates of association and dissociation were calculated to be 5.98 X 10(7) M-1 min-1 and 0.578 min-1, respectively. Binding of [125I]iodo-Tyr1-SRIF is not inhibited by morphine, beta-endorphin, [D-Ala2]Met-enkephalin, LHRH, TRH, histidylproline diketopiperazine, neurotensin, substance P, bombesin or vasoactive intestinal peptide. In contrast SRIF, [Tyr1]SRIF, and [D-Trp8,D-Cys14]SRIF displace [125I]iodo-Tyr1-SRIF binding with Ki values 0.10 +/- 0.05, 0.46 +/- 0.18, 0.05 +/- 0.01 nM, respectively. The constants of inhibition of a series of alanine monosubstituted analogs of SRIF are correlated (r = 0.89) with their biological potency on GH secretion. Furthermore, postnatal development patterns of [125I]iodo-Tyr1-SRIF binding sites follow the ability of SRIF to inhibit GH release. Thus, [125I]iodo-Tyr1-SRIF binding to adenohypophyseal membranes seems to reflect interaction with SRIF receptors on adenohypophyseal cells. Since biological effects of the peptide have been reported on GH, thyrotropin-stimulating hormone, and PRL secretion, further studies are required to determine the cell types upon which this binding occurs.

Role of charge transfer interactions in photoreactions III: inorganic anion-induced intersystem crossing of stilbene-like molecules

The effect of halide and thiocyanate anions on the fluorescence and photoisomerization of trans-stilbene, styrylnaphthalenes and their monosubstituted aza analogues was studied in a 2:3 acetonitrile; water mixture. The quenching of the fluorescence depends on the oxidation potential of the perturbers and is generally accompanied by anion-induced population of the reactive triplet state of the fluorescers. The limiting induced quantum yield for the trans → cis photoisomerization in the triplet manifold reachrs its maximum value of about 0.5 for the iodine anion which has the best heavy atom and electron donor properties.

ChemInform Abstract: CATECHOLAMINE ANALOGS AS POTENTIAL ANTITUMOR AGENTS. II

AbstractDas Trimethoxybenzylamin (II) wird aus dem Amid (Ia) bzw. dem Nitril (Ib) hergestellt und in das Trihydroxybenzylamin‐hydroiodid (III) übergeführt.

Paramagnetic adducts between manganese-centred radicals and nitro derivatives. A new class of manganese-containing radicals

The photolytic or thermal reaction of pentacarbonylmanganese radicals with either aromatic or aliphatic nitro compounds in the presence of PBu 3, and in one case of pyridine, gives spin adducts which have been studied by ESR spectroscopy. On the basis of the spectral parameters these paramagnetic species, which represent the first example of a new class of transition metal-containing radicals, have been assigned a cyclic structure, with the manganese atom acting as a bridge between the two oxygens of the nitro group; this implies the loss of a CO unit during complexation. The role of the phosphine in stabilizing these radicals by replacing one or two CO moieties is critical; doubly-substituted species are much more persistent than their mono-substituted analogues. In the absence of PBu 3 the corresponding paramagnetic adduct could be observed only with 2-methyl-2-nitropropane.

Catecholamine Analogs as Potential Antitumor Agents

The structural requirements for murine P-388 leukemia activity in the dopamine series were investigated. Eight of the 31 analogs evaluated possessed reproducible antitumor activity. The ortho-aromatic hydroxyl groups were required for activity, but the aminoethyl side chain was not crucial since this group could be replaced by methyl or amino-methyl groups with the retention of activity. The lack of activity of O-alkylated and monosubstituted analogs suggests that o-quinone formation may be important for activity, a possibility supported by the observed P-388 activity of 5-hydroxydopamine compared with the inactivity of the 6-hydroxy isomer.

Carbon-13 nuclear magnetic resonance spectral study of some isomeric derivatives of 2-methoxytropone. Troponoid-II

The 13C nmr spectra of several isomeric monosubstituted derivatives of 2-methoxytropone together with some dibromo derivatives have been obtained and analysed. Substituent parameters were defined and shown to exhibit additivity. Differences with corresponding parameters for monosubstituted benzene analogs suggest proximity interactions between the 3-substituents and the 2-OCH3 group as well as between 7-substituents and the adjacent carbonyl group. The data indicates that the OCH3 group is a convenient probe to investigate the orientation of mesomeric electronic charge transfer to the various carbons of the tropone seven-membered ring. Finally, it is demonstrated that 13C nmr is quite useful to distinguish between the various substituted 2-methoxytropones.

Dopamine vascular actions of N-substituted derivatives of 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN)

N-ethyl, N-n-propyl, N-n-butyl, N,N-di-n-propyl and N-n-propyl-N-n-butyl derivatives of 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphahalene (ADTN) were screened for dopamine vascular agonist activity. Effects of intra-arterial injections of the drugs on renal and femoral blood flow were measured in pentobarbital-anesthetized dogs before and after phenoxybenzamine (POB), 5–10 mg/kg. All ADTN derivatives were more potent vasoconstrictors than dopamine (DA) before POB. The di-substituted analogs were approximately 1 4 and the mono-substituted derivatives were about 1 16 as active as norepinephrine as vasoconstrictors. After POB the two di-substituted analogs were about 1 4 as active as DA in causing renal vasodilation. The three mono-substituted analogs produced relatively minor and inconsistent effects on renal blood flow, and were more than 100 times less effective than DA as vasodilators. The two di-substituted analogs markedly increased blood pressure with little effect on cardiac contractility in doses up to 32 μg/kg; whereas, the threshold dose of DA is 4–8 μg/kg. This and our previous results show that structure activity relationships of DA and ADTN, a semi-rigid analog of DA, are similar. However, the rigid analogs tend to be more potent vasoconstrictors than their flexible chain homologs.

Reactions of palladium(II) with organic compounds. Part II. Oxidation of some benzenoid compounds in trifluoroacetic acid

Benzene, some monosubstituted benzenes, and di- and poly-methylated benzenes are readily oxidised by palladium(II) in trifluoroacetic acid. Benzene and most monosubstituted analogues give mainly or solely biaryls, as do o-xylene, m-xylene, and hemimellitene (1,2,3-trimethylbenzene). Most of the possible isomers were found in each case but the predominant ones are those in which one of the aryl groups is bonded to the second through the position most susceptible to electrophilic attack. Toluene, ethylbenzene, p-xylene, and pseudocumene (1,2,4-trimethylbenzene) give, in addition, diarylmethanes, and from mesitylene and durene (1,2,4,5-tetramethylbenzene) these latter compounds were the only products detected. Diarylmethane formation, in most cases, was of necessity selective but, even in those instances where more than one such compound might have been expected, only the anticipated product of electrophilic arylmethylation was observed. Mechanisms which account for the formation of the two types of product are discussed.

Kinetics and mechanism of the formation of hydrazides from hydrazidic halides

In aqueous dioxan or acetone, N-aryl-hydrazidic bromides (α-bromoarylidenehydrazines) are converted into the corresponding benzhydrazides. The kinetics of the conversion have been studied in dioxan–water (4 : 1) at 25° and a Hammett ρ value of –0·63 was obtained for variation of the N-aryl substituent. The observation of a primary salt effect, a large common-ion effect, and an m value of 0·89 for solvent variation support a mechanism involving rate-determining ionization (azocarbonium ion formation). The solvolysis of an NN-disubstituted hydrazidic bromide (which unlike the mono-substituted analogues cannot form a 1,3-dipolar ion) was studied in buffered solution; its reactivity paralleled that of the mono-substituted compounds. Steric inhibition of azocarbonium ion formation is marked since cyclic hydrazidic bromides (e.g. 3-bromo-2-pyrazoline) failed to react in aqueous solvents even under forcing conditions.