Determination of the beta-blocker carteolol in human plasma by a sensitive gas chromatographic-negative-ion chemical ionization high-resolution mass spectrometric method.

A specific and sensitive gas chromatographic-high-resolution mass spectrometric method for the determination of 5-(3-tert.-butylamino-2-hydroxy)propoxy-3,4-dihydrocarbostyril (carteolol), which is a beta-blocker giving depression of intraocular pressure, was developed to elucidate the pharmacokinetics of its ophthalmic application. Carteolol has been determined by high-performance liquid chromatography but with less satisfactory sensitivity. Carteolol was derivatized with pentafluorobenzoyl (PFB) amide followed by dimethylethylsilyl (DMES) ether, resulting in a high negative-ion current. The PFB-DMES derivative of carteolol was determined by the gas chromatography-negative-ion chemical ionization mass spectrometry (GC-NICI-MS) using selected-ion monitoring at low and high mass spectrometric resolution. the detection limit was less than 100 fg when the fragment ion was monitored at m/z 552.2067 in the NICI mode using methane as a reagent gas. The quantification limit of carteolol in human plasma with this method was less than 30 pg/ml. The proposed GC-MS method is considered to have sufficient specificity and sensitivity to study the pharmacokinetics of carteolol used as an ophthalmic solution.

New norepinephrine potentiators: synthesis and structure-activity relationships of a series of 4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ols.

A variety of 1,2,3,4-tetrahydroisoquinolin-4-ols (1-6) were prepared as part of our search for new norepinephrine (NE) potentiators and to clarify the structure-activity relationships. These compounds and some previously prepared compounds were compared with 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ol (PI-OH) (1a) for ability to potentiate NE. The potency, for 2-substitution, was found to be in the order: Me > Et > iso-Pr > H. The compounds substituted by a halogen atom at the para position in the 4-phenyl group of PI-OH showed greater activities than did PI-OH, and the observed order of potency for the substitution was Cl > Br > F > H. The compound (4) methylated at the hydroxy group in PI-OH had greatly diminished activity. Although the desoxy compound (6) of PI-OH potentiated the response to NE at low concentrations, the potentiation was progressively masked by an inhibitory activity as the concentration of 6 was increased. In addition, the 4-cyclohexyl analogue (5) failed to potentiate NE. These results show the importance of the beta-phenylethanolamine skeleton of PI-OH for producing NE potentiation without accompanying inhibitory action. The racemic 4-chlorophenyl analogue (2a) was resolved by HPLC to (R)-(+)-2a and (S)-(-)-2a. The NE-potentiating activity was found to reside exclusively in (R)-(+)-2a, which had the highest activity among compounds tested in this study; the activity ratio was 25 at 3 x 10(-6) M. The antidepressant activity of racemic 2a was evaluated by a forced swimming test.(ABSTRACT TRUNCATED AT 250 WORDS)

Resolution, absolute stereochemistry, and enantioselectivity of 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ol.

Racemic 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ol (PI-OH) (1) was found to be an effective potentiator of the contractile response of norepinephrine (NE) on rat anococcygeus muscle. This paper describes the resolution of racemic PI-OH by an HPLC method to give the optically pure enantiomers (+)-1 and (-)-1. The absolute configuration of (+)-1 was R as determined by CD analysis and by single-crystal X-ray diffractometric analysis of the methiodide 6 derived from (+)-1. Examination of the effects of the enantiomers to potentiate the contraction of the rat anococcygeus muscle by NE showed a high degree of enantioselectivity. The NE potentiation was found to reside exclusively in (R)-(+)-1; the activity ratio being 21 at 3 x 10(-6) M, whereas (S)-(-)-1 did not show any potentiating and inhibiting activity.