- Synthesis and Binding Affinities of Cyclic and Related Linear Analogues of CCK8 Selective for Central Receptors
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To investigate the role of the sulfate group and the influence of cyclization on the biological properties of conformationally constrained CCK8 analogues, three series of compounds were synthesized: (1), (2), and Boc-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (3) (series A); (4), (5), Boc-D-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (6), and Boc-D-Glu-Tyr(SO3H)-Nle-D-Nle-Trp-Nle-Asp-Phe-NH2 (7) (series B); and (8), (9),and Boc-γ-D-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (10) (series C).The selectivity of these peptides was studied by measuring their ability to displace propionyl-CCK8 from guinea pig brain and pancreatic membranes.All the peptides displayed low affinities (KI values around 10-6 M) for the pancreatic receptors (A type).In contrast, both sulfated and nonsulfated cyclic analogues displayed high affinities for central-type binding sites (B type), especially compounds belonging to series C I(8) = 4.7 nM and KI(9) = 0.56 nM>.In all series the linear analogues had relatively poor affinities (KI ca. 300 nM) for B-type receptors.Compound 9 was the most potent (KI = 0.56 nM) and selective I(pancreas)/KI(brain) = 4464> for central-type CCK receptors of guinea pig.The cyclization of the N-terminal region of CCK8 permits one therefore to obtain probes for central receptors, and small changes directed toward the cyclic part modulate the affinity for these receptors.
- Charpentier, Bruno,Dor, Adeline,Roy, Pierre,England, Patrick,Pham, Hung,et al.
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p. 1184 - 1190
(2007/10/02)
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- Structure-Activity Relationships of Pyrimidine Nucleosides as Antiviral Agents for Human Immunodeficiency Virus Type 1 in Peripheral Blood Mononuclear Cells
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The structure-activity relationships of several pyrimidine nucleosides related to 3'-azido-3'-deoxythymidine (AZT) were determined in human immunodeficiency virus type 1 (HIV-1) infected human peripheral blood mononuclear cells.These studies indicated tha
- Chu, Chung K.,Schinazi, Raymond F.,Ahn, Moon K.,Ullas, Giliyar V.,Gu, Zi P.
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p. 612 - 617
(2007/10/02)
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- 3'-Substituted 2',3'-Dideoxynucleoside Analogues as Potential Anti-HIV (HTLV-III/LAV) Agents
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A series of 2',3'-unsaturated and 3'-substituted 2',3'-dideoxynucleoside analogues of purines and pyrimidines have been synthesized and evaluated for their inhibitory activity against human immunodeficiency virus (HIV).The 2',3'-unsaturated analogues of 2',3'-dideoxycytidine (ddeCyd) and 2',3'-dideoxythymidine (ddeThd), 3'-azido-2',3'-dideoxythymidine (AzddThd), 3'-fluoro-2',3'-dideoxythymidine, 2',3'-dideoxycytidine (ddCyd), and 2',3'-dideoxyadenosine (ddAdo) emerged as the most potent inhibitors of HIV-induced cytopathogenicity in the human T lymphocyte cell lines ATH8 and MT4.In ATH8 cells ddCyd, ddeCyd, and ddAdo had the highest therapeutic index whereas in MT4 cells AzddThd, ddThd, ddCyd, and ddAdo were the most selective.Derivatives from ddThd in which the substituent group was linked to the 3'-carbon atom via a thio, sulfonyl, or oxygen bridge were far less inhibitory to HIV than was AzddThd.
- Herdewijn, Piet,Balzarini, Jan,Clerq, Erik De,Pauwels, Rudi,Baba, Masanori,et al.
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p. 1270 - 1278
(2007/10/02)
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- 2',3'-dideoxy-5-substituted uridines and related compounds as antiviral agents
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A compound which exhibits antiviral activity towards HTLV-III/LAV, having the formula: STR1 wherein R4 is O or NH; R5 is a C2-4 alkyl group or a C3-4 cycloalkyl group, wherein said alkyl group or cycloalkyl grou
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