normotensive

RO 46-8443 is the first non-peptide endothelin ETB receptor selective antagonist. RO 46-8443 displays up to 2000-fold selectivity for ETB receptors both in terms of binding inhibitory potency and functional inhibition.

Urocortin II, a neuropeptide hormone within the corticotropin-releasing factor (CRF) family—which comprises mammalian CRF, urocortin I, urocortin III, frog sauvagine, and piscine urotensin I—displays 34, 43, and 37-40% sequence homology with rat and human CRF, human urocortin I, and human urocortin III, respectively. This compound enhances rabbit ventricular myocyte shortening and relaxation in both a time- and concentration-dependent manner. In vivo studies reveal that urocortin II lowers arterial blood pressure in both normotensive and spontaneously hypertensive rats through peripheral CRF2 receptor agonism, inducing dose-dependent tachycardia and hypotension at doses of 3 and 30 pmol/kg. Additionally, it mitigates the visceral pain response to colorectal distension at 10 and 20 μg/kg in conscious rats and delays gastric emptying in mice.

3alpha-Dihydrocadambine exhibits dose-dependent hypotensive and anti-hypertensive effects in anesthetized normotensive rats and in conscious spontaneously hypertensive rats.

Quinapril-d5 is intended for use as an internal standard for the quantification of quinapril by GC- or LC-MS. Quinapril is a prodrug form of the angiotensin converting enzyme (ACE) inhibitor quinaprilat. In vivo, quinapril reduces mean arterial pressure in renal hypertensive and spontaneously hypertensive rats. It inhibits angiotensin I-induced pressor responses in normotensive rats and dogs. Quinapril prevents left ventricular heart failure in CHF 14.6 cardiomyopathic hamsters. Formulations containing quinapril have been used in the treatment of hypertension, heart failure, and diabetic nephropathy.

BAY-747 (BAY 1165747) is an orally administered, brain-penetrant compound that stimulates soluble guanylate cyclase (sGC). It effectively counteracts memory impairments induced by L-NAME, improves cognitive performance in rats during the object location task (OLT), reduces blood pressure in conscious normotensive and spontaneously hypertensive rats (SHR), and enhances skeletal muscle function in the mdx mTRG2 mouse model of Duchenne muscular dystrophy (DMD) [1] [2] [3].

15(S)-Latanoprost is an analog of latanoprost in which the hydroxyl at carbon 15 is inverted relative to latanoprost. The IC50 values for the free acid forms of latanoprost and 15(S)-latanoprost were determined to be 3.6 nM and 24 nM, respectively, in a FP receptor binding assay using the cat iris sphincter muscle. A 3 μg dose of 15(S)-latanoprost caused a 1 mmHg reduction of IOP in normotensive cynomolgus monkeys. 15(S)-Latanoprost is a potential impurity in most commercial preparations of the latanoprost bulk drug product.

GAT564 (Compound 15d) is a highly effective allosteric modulator of the cannabinoid 1 receptor (CB1R), with EC50 values of 87 nM for cAMP and 320 nM for β-arrestin2. It significantly enhances the binding of orthosteric ligands to hCB1R and exhibits remarkable efficacy as a topical agent, significantly reducing intraocular pressure (IOP) in an ocular normotensive murine model of glaucoma [1].

AR-13324 analog mesylate, an inhibitor of Rho-kinase and the norepinephrine transporter, reduces intraocular pressure in normotensive monkey eyes.

Proadrenomedullin N-terminal 12 peptide (PAMP-12), an endogenous fragment originating from the adrenal medulla and spanning amino acids 9-20 of human PAMP-20, plays a role in causing hypotension. It functions as an agonist for the MAS-related G protein-coupled receptor family member X2 (MRGPRX2), inhibiting forskolin-stimulated cAMP accumulation in CHO cells expressing human MRGPRX2 (EC50 = 57.2 nM) and selectively prompting calcium mobilization in these cells (EC50 = 41 nM), but not in cells expressing MRGPRX1, MRGPRX3, or MRGPRX4 at 1 µM. As an antagonist of nicotinic acetylcholine receptors (nAChRs), PAMP-12 obstructs carbachol-triggered catecholamine release and the influx of calcium and sodium (IC50s = 1.3, 0.39, and 0.87 µM, respectively) in primary bovine adrenal chromaffin cells, with no effect on histamine-induced responses (IC50s = >1 µM for all). Additionally, it decreases mean arterial blood pressure in normotensive rats at doses ranging from 10 to 50 nmol/kg.

Arecaidine propargyl ester is an agonist of M2muscarinic acetylcholine receptors (mAChRs).1It selectively binds to M2over M1, M3, M4, and M5mAChRs in CHO cells expressing the human receptors (Kis = 0.0871, 1.23, 0.851, 0.977, and 0.933 μM, respectively). Arecaidine propargyl ester induces contractions in isolated guinea pig atrium (pD2= 8.67). It induces apoptosis and the production of reactive oxygen species (ROS) in U87 and U251 glioblastoma cells when used at a concentration of 100 μM.2Arecaidine propargyl ester decreases mean arterial blood pressure in normotensive cats (ED25= 1.9 nmol/kg).3It is toxic to house flies (Musca) when administered at a dose of 75 μg/fly.4 1.Scapecchi, S., Matucci, R., Bellucci, C., et al.Highly chiral muscarinic ligands: the discovery of (2S,2’R,3’S,5’R)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine 3-sulfoxide methyl iodide, a potent, functionally selective, M2 partial agonistJ. Med. Chem.49(6)1925-1931(2006) 2.Di Bari, M., Tombolillo, B., Conte, C., et al.Cytotoxic and genotoxic effects mediated by M2 muscarinic receptor activation in human glioblastoma cellsNeurochem. Int.90261-270(2015) 3.Porsius, A.J., and Van Zwieten, P.A.Central action of some cholinergic drugs (arecaidine esters) and nicotine on blood pressure and heart rate of catsProg. Brain Res.47131-135(1977) 4.Honda, H., Tomizawa, M., and Casida, J.E.Insect muscarinic acetylcholine receptor: Pharmacological and toxicological profiles of antagonists and agonistsJ. Agric. Food Chem.55(6)2276-2281(2007)

Fosinopril-d7 is intended for use as an internal standard for the quantification of fosinopril by GC- or LC-MS. Fosinopril is a prodrug form of the angiotensin-converting enzyme inhibitor fosinoprilat. Oral administration of fosinopril inhibits angiotensin I-induced pressor responses in normotensive rats, dogs, and monkeys when administered at doses of 15, 15, and 10 µmol/kg, respectively. Fosinopril reduces fractional shortening and decreases left ventricular size in a porcine model of congestive heart failure. Formulations containing fosinopril have been used in the treatment of hypertension and congestive heart failure.

Pentoprilat is a member of a series of l-glutarylindoline-2(S)-carboxylic acid derivatives. Pentopril was evaluated as an inhibitor of a cell-free preparation of angiotensin-converting enzyme (ACE) isolated from rabbit lung. Intravenous administration of incremental doses of pentopril to anesthetized normotensive rats produced a dose-related inhibition of angiotensin I (AI) pressor responses. The onset of inhibition of the A1 pressor response was rapid, and substantial inhibition occurred at 5 min after administration of the ACE inhibitors. Pentopril hydrolyzed in vivo to the biologically active free-acid form of CGS 13934. It was well tolerated in normal volunteers and hypertensive patients. Pentopril was developed for the treatment of both hypertension and congestive heart failure. Pentopril produced little clinical improvement and no biochemical improvement in a patients with rheumatoid arthritis.