Certain phenyl-substituted hydrocarbons of environmental concern have the potential to disrupt the endocrine system of animals, apparently in association with their estrogenic properties. Competition with natural estrogens for the estrogen receptor is a possible mechanism by which such effects could occur. We used comparative molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (QSAR) paradigm, to examine the underlying structural properties of ortho-chlorinated hydroxybiphenyl analogs known to bind to the estrogen receptor. The cross-validated and conventional statistical results indicate a high degree of internal predictability for the molecules included in the training data set. In addition to the phenolic (A) ring system, conformational restriction of the overall structure appears to play an important role in estrogen receptor binding affinity. Hydrophobic character as assessed using hydropathic interaction fields also contributes in a positive way to binding affinity. The CoMFA-derived QSARs may be useful in examining the estrogenic activity of a wider range of phenyl-substituted hydrocarbons of environmental concern.ImagesFigure 1.Figure 2.

Background Observational studies have reported an inverse association between dietary protein intake and blood pressure (BP). We compared the effect of soy protein, milk protein, and carbohydrate supplementation on BP among healthy adults. Methods and Results We conducted a randomized double-blind crossover trial with 3-intervention phases among 352 adults with prehypertension or stage-1 hypertension in New Orleans, Louisiana and Jackson, Mississippi from September 2003 to April 2008. The trial participants were assigned to take 40 grams/day of soy protein, milk protein, or carbohydrate supplementation each for 8 weeks in a random order. A 3-week washout period was implemented between the interventions. Three BPs were measured at 2 baseline and 2 termination visits during each of 3 intervention phases using a random-zero sphygmomanometer. Compared to carbohydrate controls, soy protein and milk protein supplementations were significantly associated with −2.0 mmHg (95% confidence interval −3.2 to −0.7, p=0.002) and −2.3 mmHg (−3.7 to −1.0, p=0.0007) net change in systolic BP, respectively. Diastolic BP was also reduced but this change did not reach statistical significance. There was no significant difference in the BP reductions achieved between soy or milk protein supplementation. Conclusions The results from this randomized controlled trial indicate that both soy and milk protein intake reduce systolic BP compared to a high glycemic index refined carbohydrate among patients with prehypertension and stage-1 hypertension. Furthermore, these findings suggest that partially replacing carbohydrate with soy or milk protein might be an important component of nutrition intervention strategies for the prevention and treatment of hypertension.

New 1-phenyl-1,2,3,4-tetrahydroisoquinolines and related 5,6,8,9-tetrahydro- 13bH-dibenzo[a,h]-quinolizines were prepared as ring-contracted analogs of the prototypical 1-phenyl-2,3,4,5-tetrahydrobenzazepines (e.g., SCH23390) as a continuation of our studies to characterize the antagonist binding pharmacophore of the D1 dopamine receptor. Receptor affinity was assessed by competition for [3H]SCH23390 binding sites in rat striatal membranes. The 6-bromo-1-phenyltetrahydroisoquinoline analog 2 of SCH23390 1 had D1 binding affinity similar to that for the previously reported 6-chloro analog 6, whereas the 6,7-dihydroxy analog 5 had significantly lower D1 affinity. Conversely, neither 6-monohydroxy- (3) nor 7-monohydroxy-1-phenyltetrahydroisoquinolines (4) had significant affinity for the D1 receptor. These results demonstrate that 6-halo and 7-hydroxy substituents influence D1 binding affinity of the 1-phenyltetrahydroisoquinolines in a fashion similar to their effects on 1-phenyltetrahydrobenzazepines. The conformationally constrained 3-chloro-2-hydroxytetrahydrodibenzoquinolizine 9 had much lower affinity relative to the corresponding, and more flexible, 6-chloro-7-hydroxy-1-phenyltetrahydroisoquinoline 6. Similarly, 2,3-dihydroxytetrahydrodibenzoquinolizine 10 had much lower D1 affinity compared to dihydrexidine 14, a structurally similar hexahydrobenzo[a]phenanthridine that is a high-affinity full D1 agonist. Together, these data not only confirm the effects of the halo and hydroxy substitutents on the parent nucleus but demonstrate the pharmacophoric importance of both the nitrogen position and the orientation of the accessory phenyl ring in modulating D1 receptor affinity and function. Molecular modeling studies and conformational analyses were conducted using the data from these new analogs in combination with the data from compounds previously synthesized. The resulting geometries were used to refine a working model of the D1 antagonist pharmacophore using conventional quantitative structure-activity relationships and three-dimensional QSAR (CoMFA).