An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Follicle-stimulating hormone (FSH) is essential for primate reproduction, acting via the FSH-receptor (FSHR) which is expressed in Sertoli and granulosa cells only. Despite its highly specific expression pattern, knowledge of the FSHR promoter and transcriptional regulation is still very limited. To gain insights into the regulatory elements controlling FSHR expression we characterized the core promoter activity of all important primate lineages including human. We isolated DNA fragments covering nucleotides -1 to -257 relative to the translational start site of the human, chimpanzee (Pan troglodytes), bonobo (Pan paniscus), cynomolgus monkey (Macaca fascicularis), marmoset (Callithrix jacchus) and lemur (Microcebus murinus) FSHR gene. The DNAs were cloned into the pGL3 vector to drive the expression of the luciferase reporter in transiently transfected COS7 and SK11 (mouse Sertoli) cell lines. Finally relative luciferase activity (RLA) was determined. Promoter activities varied significantly between species. Compared to the human FSHR promoter the chimpanzee displayed a 3.7-fold higher RLA, while for the bonobo only a 0.5 RLA was detected. The other primates displayed promoter activities similar to the human. Comparison of the human, chimpanzee and bonobo nucleotide sequences revealed only very few mismatches. Subsequent in-vitro mutagenesis of the human FSHR core promoter introducing one selected chimpanzee-specific alteration caused a significant 5-fold increase in RLA. Introducing the human nucleotide into the chimpanzee promoter decreased promoter activity to the bonobo wildtype level. Sequence analysis identified a binding site for ETS transcription factors to be involved, hitherto unknown for the FSHR promoter. Although FSHR promoters show very high degrees of sequences homology among primates, single nucleotide changes may have significant impact on FSHR promoter activities. Thus comparative functional studies using closely related species could yield important insights on different regulatory promoter elements within the same gene.
N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydro naphthalen-1-yl] methanesulfonamide hydrobromide (A-61603) is a novel and potent alpha-adrenoceptor agonist. In radioligand binding assays, the compound is at least 35-fold more potent at alpha 1A/a receptors than at alpha 1b or alpha 1d sites. In fibroblast cells transfected with alpha 1a receptors, A-61603 more potently stimulates phosphoinositide hydrolysis than norepinephrine, and is antagonized by prazosin. A-61603 is less potent in cells transfected with alpha 1b or alpha 1d receptors. A-61603 is a potent agonist at alpha 1A receptors in rat vas deferens (200- to 300-fold more potent than norepinephrine or phenylephrine, respectively) and in isolated canine prostate strips (130- to 165-fold more potent than norepinephrine or phenylephrine, respectively). In contrast, A-61603 is only 40-fold more potent than phenylephrine at alpha 1B sites in rat spleen and 35-fold less potent at rat aortic, alpha 1D sites. In an in vivo dog model, A-61603 raises intraurethral prostatic tone to a greater extent than mean arterial blood pressure. A-61603 induces a pressor response in conscious rats at doses 50- to 100-fold lower than phenylephrine, and the response is not attenuated by pretreatment with CEC, whereas YM-617 causes a 100-fold shift in the response. These results indicate that A-61603 is a potent adrenergic agonist, selective for alpha 1A/a receptors, and may prove a useful probe for studies of adrenergic function and alpha 1 adrenoceptor regulation of physiological functions.
ABBOTT-81282, 4-{N-butyl-N-[(2'-[1H-tetrazol-5yl]biphenyl-4-yl)meth-yl] amino}pyrimidine-5-carboxylic acid is a novel nonpeptide angiotensin II (All) antagonist. In vivo studies were performed to evaluate ABBOTT-81282 for its antihypertensive effect, pharmacological mechanism(s) of action, and cardiovascular safety. In the conscious renal artery-ligated (RAL) hypertensive rat, a model of high renin hypertension, ABBOTT-81282 (1-10 mg/kg p.o. and 0.1–1.0 mg/kg i.v.) lowered mean arterial pressure (MAP) in a dose-dependent manner with the ED3o values of 2.2 mg/kg for p.o. administration and 0.08 mg/kg for i.v. administration. At 10 mg/kg p.o., ABBOTT-81282 lowered blood pressure in the RAL rat (ΔMAP 66 ± 9 mm Hg from control MAP 167 ± 7 mm Hg, n = 6) to a normotensive level (MAP, 115 + 5 mm Hg) for greater than 24 h and did not change heart rate. The i.v. administration of 1 mg/kg of ABBOTT-81282 also produced a sustained, long-lasting decrease (ΔMAP 27∼52 mm Hg) in blood pressure that was significantly different from the vehicle group at 8 h postdosing (143 ± 3 mm Hg, n = 4 for ABBOTT-81282 vs. 181 + 3 mm Hg, n = 6 for vehicle group, p < 0.01). When blood pressure in the renal hypertensive rat was maximally lowered (ΔMAP 72 ± 9 mm Hg, n = 4) following the 1 mg/kg i.v. dose (cumulative) of ABBOTT-81282, additional administration of captopril (3 mg/kg i.v.) produced no further decline in blood pressure. In the conscious normotensive rat, 10 mg/kg p.o. of ABBOTT-81282 had no effect on basal MAP (119 ± 3 vs. 115 ± 4 mm Hg, pre- vs. 3.5 h postdosing, n = 4) and heart rate (364 ± 18 vs. 363 ± 14 beats/min, pre- vs. 3.5 h postdosing, n = 4) but inhibited the All (0.1 μg/kg i.v.)-induced increase in MAP by 64-70%, while the MAP responses to norepinephrine (0.3 μg/kg i.v.), vasopressin (0.03 IU/kg i.v.) and bradykinin (3 μg/kg i.v.) remained intact. ABBOTT-81282 was also administered to conscious normotensive rats (n = 4) instrumented with ECG telemetry transmitters. At an i.v. dose of 10 mg/kg, which is 125 times greater than the i.v. ED30, ABBOTT-81282 caused a minimal decrease (<14%) in MAP and had no effect on ECG waveforms. These data demonstrate that ABBOTT-81282 is a safe and efficacious antihypertensive agent with selective All antagonism. ABBOTT-81282 may have potential for clinical use in the treatment of hypertension.
OBJECTIVE To compare in vivo the potency and bladder‐vascular selectivity of ATP‐sensitive potassium channel openers (KCOs) (–)‐cromakalim, WAY‐133537 and ZD6169 and a muscarinic antagonist, tolterodine in rats. MATERIALS AND METHODS Bladder and arterial pressures were monitored simultaneously, before and after increasing intravenous doses of compounds, in each of two urethane‐anaesthetized rat bladder hyperactivity models: spontaneous non‐voiding myogenic contractions secondary to partial outlet obstruction and volume‐induced neurogenic contractions. RESULTS (–)‐Cromakalim, WAY‐133537 and ZD6169 caused a dose‐dependent suppression of spontaneous contractions in the obstructed model, with a 50% inhibition of the contraction area under the curve at doses of 0.06, 0.14 and 2.4 µmol/kg (intravenous), respectively. Corresponding decreases in mean arterial pressure at these effective doses were 24%, 15% and 15%, respectively. The KCO potency rank order was the same and their relative potency highly comparable in the neurogenic model. There was complete inhibition of spontaneous contractions in obstructed rats at doses corresponding to ≈ 50% inhibition of the neurogenic contractions. While tolterodine caused a dose‐dependent inhibition of contractions in the neurogenic model, it was ineffective at inhibiting non‐voiding contractions in obstructed rats. CONCLUSIONS All KCOs tested caused significant decreases in arterial pressure at doses effective on the bladder in the model of obstructive instability, suggesting a lack of bladder‐vascular selectivity. Similar KCO potency in both assays suggests no appreciable changes in K ATP channel function as a result of partial outlet obstruction.
We characterize the in vitro and in vivo pharmacology of CHIR 2279, an N-substituted glycine peptoid previously identified from a combinatorial library as a novel ligand to alpha 1-adrenoceptors. Competitive receptor-binding assays with [3H]prazosin showed that CHIR 2279 was similar to prazosin in binding to alpha 1A (rat submaxillary), alpha 1a, alpha 1b, and alpha 1 d (cDNA expressed in LTK- cells) with high and approximately equipotent affinity. Ki values for CHIR 2279 ranged from 0.7 to 3 nM, and were 10-fold weaker than with prazosin. Functional assays for postsynaptic alpha 1-adrenoceptors showed CHIR 2279 was approximately equipotent in antagonizing agonist-induced contractile responses with rat was deferens (alpha 1A), canine prostate (alpha 1A), rat spleen (alpha 1B) and rat aorta (alpha 1D). The pA2 for CHIR 2279 averaged 7.07 in these assays, indicating a 10- to 100-fold lower in vitro potency than prazosin. In dogs, CHIR 2279 antagonized the epinephrine-induced increase in intraurethal pressure (pseudo pA2, 6.86) and in rats antagonized the phenylephrine-induced increase in mean arterial blood pressure. In rats and guinea pigs, CHIR 2279 induced a dose-dependent decrease in mean arterial blood pressure without eliciting the tachycardia commonly observed with other alpha 1-blockers. Pharmacokinetic/pharmacodynamic modeling showed the i.v. system clearance rate of CHIR 2279 was 60 and 104 ml/min/kg in rats and guinea pigs, respectively, and the in vivo potency for mean arterial blood pressure reduction was twice as great in guinea pigs (EC50, 520 ng/ml) than rats (EC50, 1170 ng/ml).
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