ABSTRACT
Of the 42 R'-X-(p-Cl)Phe-D-Phe-Arg-Trp-NH(2) (X=CO, SO(2), PO, PS) tested at the human (h)MC1, hMC3, and hMC4 receptors (R), the most potent MC4R agonists (EC(50) of 8-20 nM) were obtained by end-capping with R'=CH(2)CHCH(2) (9), NCCH(2) (16), NH(2)COCH(2) (17), HCONHCH(2) (18), CH(3)NH (19), CH(2)CHCH(2)NH (21), 2-Th (23), PhCH(2) (30) and X=CO. These compounds possess 35-60-fold hMC4 versus hMC1Rs selectivity with urea LK-71 (19) being the most potent at hMC4R and MC4/1R selective (EC(50)=8.5 nM, MC4/1R=100). LK-75 (16) combines high potency at hMC4R and MC4/3R selectivity (EC(50)=10.5 nM, MC4/3R=290). SAR is discussed.
Subject(s)
Oligopeptides/chemical synthesis , Receptor, Melanocortin, Type 4/agonists , alpha-MSH/chemical synthesis , Humans , Oligopeptides/pharmacology , Structure-Activity Relationship , alpha-MSH/pharmacologyABSTRACT
Twenty nine analogs of a superpotent MC1R agonist LK-184 (1) were tested at human melanocortin receptors (hMC1, hMC3, and hMC4Rs). All derivatives with the spacer between the N-terminus and the aromatic ring longer or shorter than C(3) were much less potent at hMC1R than 1. Only LK-312 PhCO(CH(2))(3)CO-His-d-Phe-Arg-Trp-NH(2) (3), partially mimicking the pi-system of 1, had an EC(50) of 0.05 nM at hMC1R, which confirms the localization of the pi-binding zone of the receptor. Truncation of 1 to Ph(CH(2))(3)CO-His-d-Phe-Arg-NH(2) gave a full MC1 agonist, LK-394 (30), with an EC(50) of 5 nM and a weak partial agonism at MC3/4Rs. This suggests the existence of an additional binding site within hMC1R next to that for the core sequence His-d-Phe-Arg-Trp-NH(2).
Subject(s)
Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Receptor, Melanocortin, Type 1/agonists , Binding Sites , Humans , Kinetics , Receptor, Melanocortin, Type 1/chemistry , Structure-Activity RelationshipABSTRACT
Twenty three derivatives of the core fragment His(6)-D-Phe(7)-Arg(8)-Trp(9)-NH(2) end-capped with carboxylic and sulfonic acids were synthesized and evaluated at human melanocortin receptors (hMC1, hMC3, and hMC4Rs). The SAR within this series allowed us to map the hMCRs near the His(6) binding site and design a superpotent MC1R agonist, LK-184, Ph(CH(2))(3)CO-His-D-Phe-Arg-Trp-NH(2) (19) with EC(50) 0.01 nM (5 nM at MC3 and MC4Rs).
Subject(s)
Oligopeptides/chemistry , Oligopeptides/chemical synthesis , Receptor, Melanocortin, Type 1/agonists , Binding Sites , Carboxylic Acids/chemistry , Cell Line , Histidine/chemistry , Humans , Models, Chemical , Oligopeptides/metabolism , Oligopeptides/pharmacology , Peptide Fragments/chemistry , Protein Binding , Receptor, Melanocortin, Type 1/chemistry , Receptor, Melanocortin, Type 1/metabolism , Structure-Activity Relationship , Sulfonic Acids/chemistry , alpha-MSH/chemistryABSTRACT
Pyranosyl chlorides prepared in situ from tri-O-benzyl-D-galactal and TolSCl react with silyl enol ethers, allyltrimethylsilane, and vinyl ethers to give a mixture of beta-C-galacto and alpha-C-talopyranosides in a ratio of 19:1.
Subject(s)
Galactose/analogs & derivatives , Thiogalactosides/chemistry , Carbon/chemistry , Ether/chemistry , Galactose/chemistry , Magnetic Resonance Spectroscopy , Models, Chemical , Silanes/chemistry , Stereoisomerism , Vinyl Compounds/chemistryABSTRACT
1. Some nicotinic antagonists (piperidine and quinuclidine derivatives and bis-quaternary compounds) protect early embryos of the sea urchin Lytechinus pictus against a calcium shock evoked by ionomycin or a mixture of phorbol myristate acetate and nicotine. 2. Maximal protective potency was found for drugs that did not penetrate the plasma membrane. 3. Early sea urchin embryos have nicotinic acetylcholine receptors (nAChR) or nAChR-like structures localized on the cell surface that, apparently, take part in the control of Ca2+ influx.
