RESUMO
A series of cyclic lactam analogues of gamma-MSH (H-Tyr1-Val2-Met3-Gly4-His5-Phe6-Arg7-Trp8-Asp9-Arg10-Phe11-Gly12-OH) with a bulky hydrophobic residue in the direct proximity to the pharmacophore (Xaa-D-Phe/D-Nal(2')-Arg-Trp) were designed and synthesized by solid-phase methods. A variety of amino acids with a broad range of hydrophobic/hydrophilic properties was introduced in position 5 to further explore their complementary role in receptor selectivity. Biological evaluation of these peptides revealed several analogues with potent hMC3R agonist and hMC3R/hMC5R antagonist activities, and good receptor selectivity. Analogue 4, c[Nle-Arg-D-Phe-Arg-Trp-Glu]-NH2, was found to be a very potent and selective hMC3R agonist (EC50=1.2 nM, 112% act). In addition, analogue 13, c[Nle-Val-D-Nal(2')-Arg-Trp-Glu]-NH2, was identified as an hMC3R/hMC5R antagonist with the best selectivity against the hMC4R in this series (pA2(hMC3R)=8.4; pA2(hMC5R)=8.7). These results indicate the significance of steric factors in melanocortin receptor selectivity and suggest that introduction of bulky residues in the direct proximity to the melanocortin pharmacophore is an effective approach to design of novel hMC3R and hMC5R selective ligands.
Assuntos
Lactamas/síntese química , Peptídeos Cíclicos/síntese química , Receptor Tipo 3 de Melanocortina/agonistas , Receptor Tipo 3 de Melanocortina/antagonistas & inibidores , Receptores da Corticotropina/antagonistas & inibidores , gama-MSH/química , Adenilil Ciclases/biossíntese , Ligação Competitiva , Linhagem Celular , Desenho de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lactamas/química , Lactamas/farmacologia , Modelos Moleculares , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Ensaio Radioligante , Receptor Tipo 3 de Melanocortina/química , Receptores da Corticotropina/química , Receptores de Melanocortina , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Vitamin D deficiency or insufficiency has been observed among populations in the northern United States. However, data on the prevalence of vitamin D deficiency in areas of high sun exposure, such as Arizona, are limited. OBJECTIVE: The purpose of this study was to analyze serum 25-hydroxyvitamin D [25(OH)D] concentrations in residents of southern Arizona and to evaluate predictors of 25(OH)D in this population. DESIGN: Cross-sectional analyses of serum from participants in a colorectal adenoma prevention study were conducted to determine rates of vitamin D deficiency. Participants were categorized into 4 groups on the basis of serum 25(OH)D concentrations: <10.0 ng/mL, > or =10.0 ng/mL and <20.0 ng/mL, > or =20.0 ng/mL and <30.0 ng/mL, and > or =30.0 ng/mL. RESULTS: The mean serum 25(OH)D concentration for the total population was 26.1 +/- 9.1 ng/mL. Of 637 participants, 22.3% had 25(OH)D concentrations >30 ng/mL, 25.4% had concentrations <20 ng/mL, and 2.0% had concentrations <10 ng/mL. Blacks (55.5%) and Hispanics (37.6%) were more likely to have deficient 25(OH)D concentrations (<20 ng/mL) than were non-Hispanic whites (22.7%). Sun exposure had a greater effect on 25(OH)D in whites than in blacks and Hispanics, whereas BMI appeared to be more important in the latter groups. CONCLUSION: Despite residing in a region with high chronic sun exposure, adults in southern Arizona are commonly deficient in vitamin D deficiency, particularly blacks and Hispanics.