Higher testosterone levels are associated with unfaithful behavior in men.

BACKGROUND: Infidelity in romantic relationships is a common, but severe issue often causing breakup and severe psychological impairment. Higher levels of testosterone are related to mating-behavior, sexual desire, and infidelity in men with sexual dysfunctions. Previous studies, have insufficiently addressed the potential role of testosterone in infidelity in healthy men. METHODS: A sample of 224 middle-aged self-reporting healthy men being currently in a relationship completed questionnaires on relationship characteristics, infidelity, and provided overnight-fasting saliva samples for testosterone quantification. RESULTS: In the sample, 37.5% men answered having been unfaithful in the current relationship, while 29% were identified as fulfilling criteria for a sexual dysfunction. Adjusting for covariates, a significant positive association for the frequency of unfaithful behavior and testosterone levels emerged. Subsample analysis indicates a positive association between testosterone and infidelity only to be present in men without sexual dysfunction. CONCLUSION: Unfaithful behavior in males is associated with higher testosterone levels.

Development of potent thrombin receptor antagonist peptides.

A peptide-based structure-activity study is reported leading to the discovery of novel potent thrombin receptor antagonists. Systematic substitution of nonproteogenic amino acids for the second and third residues of the human thrombin receptor "tethered ligand" sequence (SFLLR) led to a series of agonists with enhanced potency. The most potent pentapeptide agonist identified was Ser-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH2, 9 (EC50 approximately 0.04 microM for stimulation of human platelet aggregation, approximately 10-fold more potent than the natural pentapeptide). Systematic substitution of the NH2-terminal Ser in 9 with neutral hydrophobic NH2-acyl groups led to partial agonists and eventually antagonists with unprecedented potency (greater than 1000-fold increase over the previously reported antagonist 3-mercaptopropionyl-Phe-Cha-Cha-Arg-Lys-Pro-Asn-Asp-Lys-NH2). In the series of NH2-acyl tetrapeptide antagonists, N-transcinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH 2, 41 (BMS-197525), was identified as the tightest binding (IC50 approximately 8 nM) and most potent with an IC50 approximately 0.20 microM for inhibition of SFLLRNP-NH2-stimulated platelet aggregation. Systematic single substitutions in 41 indicated that, in addition to the NH2-terminal acyl group, the side chains at the second and third positions were also responsible for important and specific receptor interactions. The p-fluoroPhe and p-guanidinoPhe residues in the second and third positions of 41 were observed to be optimal in both the agonist and antagonist series. In the case of antagonists, however, an appropriately positioned positively charged group (i.e., protonated base) at the third residue was required. In contrast, such a substitution was not required for potent agonist activity. An even more potent antagonist resulted when 41 was extended at the C-terminus by a single Arg residue giving rise to analog 90 (BMS-200261) which had an IC50 approximately 20 nM for inhibition of SFLLRNP-NH2-stimulated platelet aggregation. When the C-terminal Arg of 90 was replaced by an Orn-(Ndelta-propionyl) residue, the resulting antagonist 91 (BMS-200661) was suitable for use in radioligand binding assays (Kd = 10-30 nM). Antagonist activity observed for selected compounds was verified through secondary assays in that these analogs prevented SFLLRNP-NH2-stimulated GTPase activity in platelet membranes and Ca2+ mobilization in cultured human smooth muscle cells and mouse fibroblasts. Furthermore, this inhibition occurred at concentrations that had no effect on thrombin catalytic activity indicating a specific activity attributable to receptor binding and not enzyme inhibition.

Thrombin receptor activation by thrombin and receptor-derived peptides in platelet and CHRF-288 cell membranes: receptor-stimulated GTPase and evaluation of agonists and partial agonists.

Thrombin receptor activation, by thrombin or SFLLR-containing peptides, stimulates GTPase activity in platelet and CHRF-288 membranes. Polyclonal antibodies to peptides derived from the thrombin receptor (anti-TR52-69 and anti-TR36-49), which block many of thrombin's actions on platelets and endothelial cells, also block thrombin activation of membrane GTPase (as does thrombin active site and anion-binding exosite inhibitors). Most of the receptor-activated GTPase, stimulated by both thrombin and SFLLRNP in platelet membranes, was inhibited by prior treatment with pertussis toxin or N-ethylmaleimide, suggesting that under these conditions much of the thrombin receptor-stimulated GTPase in platelet membranes is a member of the pertussis toxin-sensitive G alpha i family. In platelet membrane preparations, the peptide agonists stimulated approximately twice as much GTPase activity as stimulated by alpha-thrombin. In contrast, the membranes prepared from CHRF-288 cells showed similar maximal SFLLRNP- and alpha-thrombin-stimulated GTPase activity. Stimulation of the platelet membrane GTPase by a variety of different peptide agonists correlated with their ability to stimulate platelet aggregation. Several peptide-based agonists were more potent than the wild-type sequence. The most potent was Ser-(p-fluoro-Phe)-(2-Napthyl-Ala)-Leu-Arg-NH2, which stimulated platelet aggregation (EC50 = 80 nM) and GTPase activity (EC50 = 110 nM). The peptide YFLLRN stimulated GTPase activity but only to approximately 40% of the activity observed with optimal concentrations of other receptor agonists. YFLLRN also limited the stimulation observed with SFLLRNP in a competitive fashion, indicating that YFLLRN is a competitive partial agonist at the thrombin receptor. These studies show that the tethered-ligand receptor mediates the GTPase activation by thrombin in platelet and CHRF-288 cell membranes, and this provides a specific, reliable, and convenient cell-free assay system with which one can evaluate agonists and partial agonists.