nifenalol (nifenalol / INPEA)

Enantioconvergent hydrolysis of m-nitrostyrene oxide at an elevated concentration by Phaseolus vulgaris epoxide hydrolase in the organic/aqueous two-phase system.

Wen Z Z, Zhao J J, Liu Y-Y YY, Zhou J-J JJ et al.

(R)-m-Nitrophenyl-1,2-ethanediol (m-NPED) is a versatile and highly value-added chiral building block for the synthesis of some bioactive compounds, such as (R)-Nifenalol. To efficiently produce (R)-m-NPED through the enantioconvergent hydrolysis of racemic (rac-) m-nitrostyrene oxide (m-NSO) using the whole resting cells of Escherichia coli/pCold-pveh2 intracellularly expressing PvEH2, an epoxide hydrolase from Phaseolus vulgaris, two reaction systems were investigated. In the Na2 HPO4 -NaH2 PO4 buffer (50 mmol l-1 , pH 7·0) system, merely 15 mmol l-1 rac-m-NSO was successfully subjected to enantioconvergent hydrolysis, producing (R)-m-NPED with 86·0% enantiomeric excess (eep ) and 177·6 mg l-1  h-1 space-time yield (STY). The experimental result indicated that there is inhibitory effect of rac-m-NSO at high concentration on PvEH2. To efficiently increase the concentration of rac-m-NSO and the STY of (R)-m-NPED, petroleum ether was first selected to construct an organic/aqueous two-phase system. Then, both the volume ratio (vo /vb ) of petroleum ether to phosphate buffer and the weight ratio (wc /ws ) of E. coli/pCold-pveh2 dry cells to rac-m-NSO were optimized as 2 : 8 and 5 : 1, respectively. In the optimized petroleum ether/phosphate buffer two-phase system, the enantioconvergent hydrolysis of rac-m-NSO at 40 mmol l-1 (6·6 mg ml-1 ) was carried out at 25°C for 12 h using 33·0 mg ml-1 vacuum freeze-dried cells of E. coli/pCold-pveh2, producing (R)-m-NPED with 87·4% eep , 82·3% yield and 502·4 mg l-1  h-1 STY. SIGNIFICANCE AND IMPACT OF THE STUDY: Epoxide hydrolases play a crucial role in producing enantiopure epoxides and/or vicinal diols. However, numerous biocatalytic reactions of organic compounds, such as epoxides, in aqueous phase suffered various restrictions. Herein, the enantioconvergent hydrolysis of rac-m-NSO in two reaction systems was investigated using the whole cells of Escherichia coli/pCold-pveh2. As a result, the concentration of rac-m-NSO and the space-time yield of (R)-m-NPED in organic/aqueous two-phase system were significantly increased, when compared with those in aqueous phase. To our knowledge, this is the first report about the production of (R)-m-NPED from rac-m-NSO at an elevated concentration by PvEH2 in the two-phase system.

Arrhythmogenic effect of beta-adrenoceptor-blocking drugs in Purkinje fibres of guinea-pig hearts.

Lemmens-Gruber R R, Zilberszac A A, Heistracher P P

The association between torsade de pointes and experimentally induced early afterdepolarizations in isolated fibres is well documented. The effect of eight beta-adrenoceptor-blocking drugs (sotalol, nifenalol, acebutolol, dichloroisoproterenol, propranolol, oxprenolol, pindolol, atenolol), and of amiodarone, was studied in isolated spontaneously beating guinea-pig Purkinje fibres by the intracellular microelectrode technique. Phase 3 early afterdepolarizations were initiated by nifenalol hydrochloride (n = 18; 10 mumol/l: 0/18, 40 mumol/l: 3/18, 80 mumol/l: 8/18, 160 mumol/l: 11/18), rac.-(+/-)-sotalol hydrochloride (n = 28; 20 mumol/l: 0/28, 40 mumol/l: 9/28, 80 mumol/l: 20/28), (R)(+)-sotalol hydrochloride (n = 12; 40 mumol/l: 1/12, 80 mumol/l: 4/12), and (S)(-)-sotalol hydrochloride (n = 10, 40 mumol/l: 1/10, 80 mumol/l: 4/10). The arrhythmogenic effect was reversible after a washout period of one hour and early after-depolarizations could be terminated by tetrodotoxin (0.4-1.6 mumol/l, n = 6). Amiodarone only induced early afterdepolarizations at a low extracellular potassium concentration of [K+]o = 1.35 mmol/l (n = 5; 150 mumol/l: 0/5, 300 mumol/l: 1/5). The initiation of early after-depolarizations by sotalol and nifenalol might be induced by an imbalance of sodium inward current and potassium outward currents, and early afterdepolarizations are blocked by tetrodotoxin.

Effects of bucumolol, nadolol and nifenalol on maximum upstroke velocity of action potential in guinea pig papillary muscles.

Ichiyama M M, Sada S S, Takahashi Y Y, Sada H H et al.

The effects of bucumolol (BUC), nadolol (NAD) and nifenalol (NIF) on contractile forces and on action potentials (APs) were investigated in isolated guinea pig atrial and papillary muscles, respectively. Log 1/ED40 values for the negative inotropic effects of these drugs were 0.097, 10 and 0.74 mmol/l in this order. BUC (50 mumol/l), NAD (0.5 mmol/l) and NIF (0.2 mmol/l) produced about 60, 20 and 20% reduction of Vmax at 1 Hz. The frequency-dependent reductions at these and higher concentrations were greatest for BUC, intermediate for NAD and least for NIF. These potencies at certain frequencies were, as a whole, consistent with log P-potency relationship established in our previous papers (Harada et al. 1981; Ban et al. 1985). The reductions of Vmax in APs in response to premature stimuli during basic stimuli at the rate of 0.25 or 0.027 Hz decayed exponentially during diastolic intervals (DI). The time constants of these decay process (tau) estimated by linear and nonlinear regression analyses and by eye were 12.2-9.6 s for BUC (50-100 mumol/l) and 2.9-4.8 s for NAD (1-2 mmol/l) and 57-87 ms for NIF (0.2-1 mmol/l). In terms of the molecular weight (MW)-log tau relationship (Ban et al. 1985), these tau values are within the 95% fiducial limit for BUC and NAD and deviated from the lower fiducial limit for NIF. The frequency-dependent reductions of Vmax by these drugs were explained in terms of a function of tau and the intercept Ao. Based on the study made by Cohen et al.(ABSTRACT TRUNCATED AT 250 WORDS)

[Action of propranolol, nifenalol, and pindolol on the lipolytic effect of adrenaline in the rat epididymis].

Sánchez-Cuadrado M C MC, Boada J J, Bayo J M JM