Non-peptidic small-molecule antagonists of the human platelet thrombin receptor PAR-1.

The thrombin receptor on human platelets is the first member identified of a new family of G-protein coupled receptors referred to as protease activated receptors (PARs). These receptors are activated by a unique mechanism involving proteolytic cleavage of a portion of the extracellular domain to generate a new N-terminus which then acts as a tethered or intramolecular ligand (agonist) for the receptor. The hexapeptide SFLLRN-NH2 comprising the new N-terminus is referred to as the Thrombin Receptor Activating Peptide, or "TRAP" Thrombin is the most potent agonist for platelet aggregation and selective blockade of the intramolecular activation step without effecting the proteolytic activity of thrombin should result in moderation of platelet activation and aggregation without interfering with the other coagulation cascade effects of thrombin. Screening of combinatorial libraries identified a novel, non-peptide PAR-1 thrombin receptor antagonist. Examination of structure-activity relationships revealed that portions of the molecule could be replaced resulting in simpler molecules of lower molecular weight that were at the same time more potent. Molecules in this series were effective antagonists of TRAP-stimulated platelet activation, but had limited activity when thrombin was the agonist. Additional directed screening and subsequent lead refinement resulted in a second series of isoxazole based compounds. Some of the resultant molecules were potent PAR-1 antagonists that were effective against both TRAP- and thrombin-stimulated receptor activation. These compounds do not inhibit the proteolytic effects of thrombin but rather interfere with the intramolecular binding of the tethered ligand (SFLLRN) to the transmembrane portion of the thrombin receptor. They represent promising leads for future explorations of antithrombotic activity of thrombin receptor antagonists.

Discovery and initial structure-activity relationships of trisubstituted ureas as thrombin receptor (PAR-1) antagonists.

Thrombin is the most potent agonist of platelet activation, and its effects are predominantly mediated by platelet thrombin receptors. Therefore, antagonists of the thrombin receptor have potential utility for the treatment of thrombotic disorders. Screening of combinatorial libraries revealed 2 to be a potent antagonist of the thrombin receptor. Modifications of this structure produced 11k, which inhibits thrombin receptor stimulated secretion and aggregation of platelets.

Preparation and evaluation of 1,3-diaminocyclopentane-linked dihydropyrimidinone derivatives as selective alpha1a-receptor antagonists.

Several 1,3-diaminocyclopentane linked alpha1a-receptor antagonists were prepared using a divergent chemical strategy that allows for rapid analysis of all stereochemical permutations for their effect on alpha1-receptor binding.

Selective alpha1a adrenergic receptor antagonists based on 4-aryl-3,4-dihydropyridine-2-ones.

A series of alpha1a receptor antagonists derived from a 4-aryl-3,4-dihydropyridine-2-one heterocycle is disclosed. Potency in the low nanomolar to picomolar range along with high selectivity was obtained. In vivo efficacy in a prostate contraction model in rats was observed with a few derivatives.

In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective alpha(1A) receptor antagonists for the treatment of benign prostatic hyperplasia.

alpha(1) Adrenergic receptors mediate both vascular and lower urinary tract tone, and alpha(1) receptor antagonists such as terazosin (1b) are used to treat both hypertension and benign prostatic hyperplasia (BPH). Recently, three different subtypes of this receptor have been identified, with the alpha(1A) receptor being most prevalent in lower urinary tract tissue. This paper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective alpha(1A) receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K(i) values for the alpha(1a) receptor subtype <1 nM while being greater than 100-fold selective versus the alpha(1b) and alpha(1d) receptor subtypes. Many of these compounds were also evaluated in vivo and found to be more potent than terazosin in both a rat model of prostate tone and a dog model of intra-urethral pressure without significantly affecting blood pressure. While many of the compounds tested displayed poor pharmacokinetics, compound 48 was found to have adequate bioavailability (>20%) and half-life (>6 h) in both rats and dogs. Due to its selectivity for the alpha(1a) over the alpha(1b) and alpha(1d) receptors as well as its favorable pharmacokinetic profile, 48 has the potential to relieve the symptoms of BPH without eliciting effects on the cardiovascular system.

A tale of two sexually transmitted diseases. Prevalences and predictors of chlamydia and gonorrhea in women attending Colorado family planning clinics.

BACKGROUND: The comparative prevalences and predictors of chlamydia and gonorrhea have not been studied in the family planning clinic population. GOALS: To determine the comparative prevalences and predictors of chlamydia and gonorrhea among Colorado family planning clinic patients. STUDY DESIGN: Cross-sectional study of public and private family planning clinic patients in Colorado tested for both chlamydia and gonorrhea (n = 12,926). RESULTS: Among women tested for both infections, the chlamydia prevalence rate was 4.5% and the gonorrhea prevalence rate was 0.5%. Multivariate analysis showed that independent predictors of chlamydia were age younger than 25 years, black or Hispanic race-ethnicity, cervical friability, mucopus, exposure to a sex partner with chlamydia, or multiple recent sex partners. Independent predictors of gonorrhea were age younger than 20 years, black or Hispanic race-ethnicity, or exposure to a sex partner with gonorrhea; adjusted odds ratios for exposure to gonorrhea and black race were the highest for either infection. CONCLUSIONS: The gonorrhea prevalence rate was very low compared to that of chlamydia in patients at Colorado family planning clinics. Cost-effective gonorrhea testing strategies are needed for this population.

PIP: In Colorado, state health department laboratory personnel used the DNA probe assay, Gen-Probe, to test specimens from 12,926 women for both Chlamydia trachomatis and Neisseria gonorrhoeae infections and from another 9416 women for Chlamydia alone. All the women had attended public and private family planning clinics state-wide during July 1994 to May 1995. Researchers conducted a comparative analysis to determine the prevalence and the predictors of each sexually transmitted disease (STD) among the family planning clinic population in Colorado. Women tested for both chlamydia and gonorrhea had a higher chlamydia prevalence rate than those tested for only chlamydia (4.5% vs. 3.5%; p 0.001). 64 (0.5%) of the women who were tested for both chlamydia and gonorrhea tested positive for gonorrhea. The gonorrhea prevalence was 9 times lower than that of chlamydia. Among the 64 women with gonorrhea, 25 (39.1%) also tested positive for chlamydia. Among the 577 women with chlamydia, 4.3% also tested positive for gonorrhea. The multivariate analysis revealed that variables independently associated with chlamydia included age under 20 or 20-24 years (odds ratio [OR] = 3.84 and 2.44, respectively), African-American or Hispanic race-ethnicity (OR = 2.41 and 1.65, respectively), cervical friability (OR = 2.26), mucopus (OR = 2.64), exposure to a sex partner with chlamydia (OR = 3.79), and multiple recent sex partners (OR = 1.4). Variables independently associated with gonorrhea included age under 20 years (OR = 3.42), African-American or Hispanic race-ethnicity (OR = 12.71 and 3.07, respectively), and exposure to a sex partner with gonorrhea (OR = 39.29). Cost-effective analyses would help determine appropriate selective screening strategies for gonorrhea. The researchers found that the criteria of urban residency, African-American race, and exposure to a sex partner with gonorrhea would involve the testing of 82% of patients, which would identify 94% of gonorrhea infections.

The college student-athlete: psychological considerations and interventions.

This article reviews the literature dealing with problems brought by student-athletes to college counseling and mental health centers. Among the issues discussed are fear of success; identity conflict; social isolation; poor athletic performance; academic problems; and career or vocational concerns. In addition, the authors examine the paradox that although athletes experience as much or more psychological distress as nonathletes, research indicates that athletes use professional services less often than nonathletes. Finally, the authors review approaches to psychological intervention, including short-term psychotherapy, very brief interventions, cognitive behavioral therapy, and career/vocational counseling, and discuss special considerations for conducting therapy with athletes.