This study examined the ex-vivo occupancy by KMD-3213 of alpha1-adrenoceptors in the prostate and other tissues of rats in terms of tissue selectivity and duration of occupancy in relation to plasma concentration. Oral administration of KMD-3213 (0.2-20.2 micromol kg(-1), 0.5 h) dose-dependently decreased [3H]prazosin binding sites (Bmax) in the prostate (42-74%) and submaxillary gland (54-88%) compared with the control value. In contrast, there was only a slight change in the Bmax values in the spleen and cerebral cortex of KMD-3213-treated rats. The alpha1-adrenoceptor occupancy in the prostate and submaxillary gland was increased, with plasma free concentration of KMD-3213 at 0.5 h after oral administration of KMD-3213 (0.6-20.2 micromol kg(-1)). The receptor occupancy in these tissues was much greater than that in the spleen, heart or cerebral cortex. After oral administration of KMD-3213 (6.1 micromol kg(-1)), the alpha1-adrenoceptor occupancy in the prostate and submaxillary gland occurred rapidly, in parallel with the rise in the plasma concentration of the drug, and it lasted for at least 24 h, despite a remarkable decrease in the plasma concentration. It is concluded that KMD-3213 may produce fairly selective and sustained occupancy of alpha1-adrenoceptors in the prostate, a target organ for treatment of bladder outlet obstruction in patients with benign prostatic hyperplasia.
Conformationally restricted peptidomimetics comprising eight stereoisomeric scaffolds with three-dimensional structural diversity were designed based on the structural features of cyclopropane, that is, cyclopropylic strain, which mimic wide-ranging tetrapeptide conformations covering β-turns through β-strands. Stereoselective synthesis of the designed peptidomimetics led to the identification of nonpeptidic melanocortin-4 receptor ligands.
The stereochemical diversity-oriented conformational restriction strategy can be an efficient method for developing specific ligands for drug target proteins, especially in cases where neither the bioactive conformation nor the pharmacophore is known. To develop potent H3 and H4 receptor antagonists, a series of conformationally restricted analogues of histamine with a chiral cis- or trans-cyclopropane structure were designed on the basis of this strategy. These target compounds with stereochemical diversity were synthesized from the versatile chiral cyclopropane units (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (6 and 7, respectively) or their enantiomers ent-6 and ent-7. Pharmacological profiles of these conformationally restricted analogues were shown to be different depending on the cyclopropane backbones. Among the analogues, (1R,2S)-2-[2-(4-chlorobenzylamino)ethyl]-1-(1H-imidazol-4-yl)cyclopropane (11a) with the (1R)-trans-cyclopropane structure has remarkable antagonistic activity to both the H3 (Ki = 8.4 nM) and H4 (Ki = 7.6 nM) receptors. The enantiomer of 11a, i.e., ent-11a, with the (1S)-trans-cyclopropane structure turned out to be a highly potent and selective H3 receptor antagonist with a Ki of 3.6 nM. Conversely, (1R,2R)-2-[(4-chlorobenzylamino)methyl]-1-(1H-imidazol-4-yl)cyclopropane (10a) with the (1R)-trans structure was selective for the H4 receptor (Ki = 118 nM) compared to the H3 receptor (Ki > 103 nM). Thus, a variety of compounds with different pharmacological profiles have been developed. These results show that when the structure of the target protein is unknown, the stereochemical diversity-oriented approach can be a powerful strategy in medicinal chemical studies.
Drug-induced photoirritation can be defined as an inflammatory reaction of the skin after topical or systemic administration of pharmaceutical substances. In many cases of drug-induced phototoxicity, skin reactions can be triggered by doses of sunlight regarded as harmless and most often in the ultraviolet A (320 – 400 nm). Several classes of drugs including antibacterials, thiazide diuretics, non-steroidal anti-inflammatory drugs, quinolones, and tricyclic antidepressants, even though nontoxic by themselves, may become reactive under exposure to environmental light, leading to undesired side effects. At least three types of drug-induced phototoxic skin reactions, including the photoirritant, photogenotoxic and photoallergic skin responses, have been recognized, and their mechanisms and pathologic features are quite different. The development of effective methodology to evaluate the photochemical/biological properties has been attempted over the past few years, since it would be a key consideration to predict and avoid the phototoxic risk in the early phase of the drug discovery process. The aim of this review is to describe the clinical features, pathogenesis and photochemical characteristics of drug-induced phototoxicity, and the current developments in research tools for predicting phototoxic potential of new drug entities are also addressed. Keywords: Phototoxicity, photoirritation, photoallergy, photogenotoxicity, reactive oxygen species
