3-Hydroxy-alpha-methyltyrosine progenitors: synthesis and evaluation of some (2-oxo-1,3-dioxol-4-yl)methyl esters.

The (5-methyl-2-oxo-1,3- dioxol -4-yl)methyl and (5-tert-butyl-2-oxo-1, 3- dioxol -4-yl)methyl esters of 3-hydroxy-alpha-methyltyrosine (methyldopa) were prepared and evaluated as progenitors of the amino acid. 1H NMR experiments reveal that the esters are converted cleanly to methyldopa and the corresponding alpha-diketone at pH 7.4, with the 5-methyl derivative undergoing hydrolysis faster than the 5-tert-butyl analogue. Bioavailability studies in dogs show that the esters, particularly the 5-methyl derivative, yield significant plasma levels of methyldopa. Both esters are orally effective antihypertensive agents in spontaneously hypertensive (SH) rats. These studies indicate that (2-oxo-1,3- dioxol -4-yl)methyl esters are viable prodrugs for the latentiation of methyldopa.

Preparation of some 10-[3-(dimethylamino)-1-propyl]-10H-pyrazino[2,3-b][1,4] benzothiazines as potential neuroleptics.

Chloro- and methyl-substituted 10H-pyrazino[2,3-b][1,4]benzothiazines were prepared and their structures determined by 13C NMR and X-ray crystallographic analysis. Alkylation afforded the 10-[3-(dimethylamino)-1-propyl] derivatives, which were compared to chlorpromazine in receptor-binding assays, in vivo behavioral tests, and electrochemical oxidation studies. In this series, the 2-chloro compound, 4c, proved to be the most effective derivative in displacing [3H]siperone, [3H]apomorphine, and [3H]prazosin radioligands from binding sites, being approximately as potent as chlorpromazine in this respect. However, none of the 10H-pyrazino[2,3-b][1,4]benzothiazines of this study were as active as chlorpromazine in in vivo tests predictive of neuroleptic activity.

Carbon-13 Fourier transform nuclear magnetic resonance. II. Ribonuclease.

High-resolution Fourier transform nuclear magnetic resonance was used to observe the natural abundance (13)C spectrum of a 0.02 M solution of bovine pancreatic ribonuclease A. Peaks assignable to only three carbons were easily observed after 10 hr of signal averaging. A number of tentative assignments were made. As expected, the (13)C spectrum was appreciably richer in detail than the corresponding proton spectrum. Natural abundance (13)C Fourier transform nmr appears to be a practical tool for the study of biopolymers in solution.

Synthesis and conformational study of a cyclic hexapeptide analog of somatostatin containing dehydrophenylalanine.

A cyclic hexapeptide analog of somatostatin, cyclo-(Pro-delta z-Phe-D-Trp-Lys-Thr-Phe) (II) has been synthesized by a combination of solid phase and solution methodology. It shows a potency for inhibition of growth hormone release in vitro about one-tenth that of the corresponding saturated analog, cyclo-(Pro-Phe-D-Trp-Lys-Thr-Phe) (I). N.m.r. studies indicate comparable backbone conformations for analogs I and II. However, the sum of our findings from biological evaluation and solution physical data suggest that on the receptor the position-7 phenyl ring of I is adopting a conformation which differs from that of one of the major solution conformers defined previously by n.m.r. studies.