Synthesis, structure and antiaggregatory effects of some N-(4,5-dihydro-1H-imidazol-2-yl)indoles.

A series of 1-(4,5-dihydro-1H-imidazol-2-yl)indole derivatives was prepared in order to evaluate their antiaggregatory activity in human platelets. The compounds 4a-m were prepared by reacting N-aryl-N-(4,5-dihydro-1H-imidazol-2-yl)hydroxylamines (2a-d) with monosubstituted acetylene derivatives 3a-b. Imidazoline derivatives 4 were further acetylated or sulfonylated to give amides 5a-c and sulfonamides 6a-c and 7a-c, respectively. Eight compounds were taken as representative aryliminoimidazoline analogs. Among them only one, 4m, showed a good concentration-dependent action against the primary or alpha 2-adrenoreceptor mediated phase of noradrenaline-induced aggregation in platelets.

Synthesis, structure, and binding of some 2-imidazolines to rat brain alfa-1 and alfa-2-adrenergic receptors.

A series of novel 2-[(2-aminophenyl)imino]imidazolinium salts 3a-d and N-benzyl-N-(4,5-dihydro-imidazol-2-yl)-O-methylhydroxylamine hydrochloride 7a-c were prepared and their structure was determined by IR and NMR spectroscopic data as well as X-ray analysis of the imidazolinium azide salt 3e. Binding evaluation for both alpha 1- and alpha 2-adrenergic receptors in rat brain preparations of these compounds and the previously described alpha-hydroxy-2-aryliminoimidazolines 11a-d, N-(4,5-dihydroimidazol-2-yl)-1,3-2-oxodihydrobenzimidazoles 12a-b, 2-amino-N-(4,5-dihydroimidazol-2-yl)-benzimidazoles 13a-b, and N-(4,5-dihydroimidazol-2-yl)-indoles 14a-b was performed. Among the compounds tested, 2-[(2-amino-4,5-dichlorophenyl)imino]imidazolinium chloride 3c showed highest binding affinity to alpha 2-adrenoreceptors (Ki = 30 nM).

Synthesis, structure, and biological activities of some N-(4,5-dihydro-1H-imidazol-2-yl)-1,3-dihydrobenzimidazole derivatives.

A series of novel N-(4,5-dihydroimidazol-2-yl)-1,3-dihydrobenzimidazole derivatives 2a-d, 3a-d and 4a-p were prepared and their structure was determined by IR and NMR spectroscopic data as well as X-ray analysis of carbonitrile 2a. The compounds were studied as potential inhibitors of the human blood platelet aggregation induced by adrenaline or ADP. Compounds of type 3 proved efficacious for the reduction of arterial blood pressure upon intravenous administration to normotensive rats.

Immunolocalization of prealbumin (transthyretin) in renal cell carcinoma.

Fourteen primary and nine metastatic renal cell carcinomas were examined with a commercially available antibody against prealbumin (transthyretin) using the avidin-biotin-peroxidase complex (ABC) technique. Twenty-two of the 23 tumours expressed prealbumin, and in 16 of them more than 50% of the tumour cells showed immunoreactivity. The same tumours were subjected to immunostaining with antibodies against low molecular weight keratin, carcino-embryonic antigen, S-100 protein and epithelial membrane antigen for comparison. We conclude that prealbumin, which was absent in 14 adenocarcinomas from other organs, should be included in the panel of markers for differentiating metastatic adenocarcinoma of renal origin from those of other primary tumours.

Hyperresponsiveness to water immersion in sodium retaining cirrhotics: the role of atrial natriuretic factor.

Cirrhotics do not respond uniformly to head-out water immersion (HWI). Some cirrhotics have an exaggerated natriuresis while others are unresponsive. We studied the humoral and urinary responses to HWI in 5 cirrhotics and compared this to 5 normals on the same 20 mM sodium intake. These cirrhotics had a documented tendency to salt and water retention but had minimal or no evidence of significant ascites. Plasma levels of atrial natriuretic factor (ANF) increased during immersion in both groups. However, the rise in plasma ANF from baseline during each hour of immersion was significantly greater in the cirrhotics (p less than 0.01), than in the normal volunteers. In these cirrhotics, HWI not only corrected the pre-immersion tendency to sodium retention, but by 3 hours had produced an exaggerated natriuretic response (p less than 0.05). It is possible that the greater risk of ANF in cirrhotics is responsible for this natriuretic response. However the reason for the larger rise in cirrhotics is unclear; presumably either a greater central redistribution of plasma volume occurs in cirrhotics following immersion, or there may be greater sensitivity of the ANF release system in cirrhotics.

Role of atrial natriuretic peptide and urinary cGMP in the natriuretic and diuretic response to central hypervolemia in normal human subjects.

The response of plasma atrial natriuretic peptide (ANP) and urinary cGMP excretion to central hypervolemia induced by water immersion was assessed twice in five healthy male subjects, once while immersed in water to the neck for 3 h and again on a control day. Plasma ANP and urinary cGMP were measured by radioimmunoassay. Compared with the control day, overall change in plasma ANP on the immersion day was significant (p less than 0.05). In response to water immersion, plasma ANP increased from a base-line level of 13.2 +/- 3.1 (mean +/- SEM) to 24.2 +/- 5.5 pg/mL by 0.5 h of immersion and was sustained at that level throughout the immersion period. Plasma ANP returned to the base-line level at 1 h postimmersion. Urinary cGMP excretion increased significantly by 1 h of immersion and was sustained at that level throughout water immersion and 1 h postimmersion (p less than 0.05). During water immersion urine flow, urinary sodium and potassium excretion, free water clearance, and osmolar clearance increased while plasma renin activity, serum aldosterone, and blood pressure fell; all changes were significant (p less than 0.05). Creatinine clearance and hematocrit did not show any significant changes. These data suggest that an increase in plasma ANP may contribute to the natriuretic and diuretic response to central hypervolemia, and that the measurement of urinary cGMP may be a valuable marker of ANP biological responsiveness.