The enantiomeric specificity of the antihypertensive activity of 1-(phenylthio)-2-aminopropane, a synthetic substrate analogue for dopamine beta-monooxygenase.
We have found that (R,S)-1-(phenylthio)-aminopropane (4a), a synthetic alternate substrate for the terminal enzyme of norepinephrine biosynthesis, dopamine beta-monooxygenase (DBM), is both an indirect sympathomimetic and a potent antihypertensive agent in spontaneously hypertensive rats. We demonstrate herein that there is a distinct enantiospecific difference in the activities of (R)-1-(phenylthio)-2-aminopropane (4b) and (S)-1-(phenylthio)-2-aminopropane (4c). We find that 4c, the more potent DBM substrate analogue, exhibits both the indirect sympathomimetic activity and the antihypertensive activity previously observed for the racemate and inhibits the active transport of catecholamines at the nerve terminal. In contrast, 4b, which is less potent as a DBM substrate or as an inhibitor of catecholamine uptake, does not exhibit an indirect sympathomimetic effect and is not an effective antihypertensive agent. These results suggest that the greater selectivity of the S enantiomer for both the catecholamine reuptake transporter and the target enzyme DBM accounts for its greater potency as an indirect-acting sympathomimetic agent as well as its activity as an antihypertensive agent. These results are also consistent with the hypothesized mechanism of action of this class of sulfur-containing DBM substrate analogues.
Herman
H H
HH
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta 30332-0400.
Husain
P A
PA
Colbert
J E
JE
Schweri
M M
MM
Pollock
S H
SH
Fowler
L C
LC
May
S W
SW
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use*; D055598:Chemical Phenomena; D002621:Chemistry; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism*; D006973:Hypertension / Q000188:drug therapy*; D007700:Kinetics; D008297:Male; D011437:Propylamines / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D011921:Rats, Inbred WKY; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D000959:Antihypertensive Agents; D011437:Propylamines; D013440:Sulfides; C067830:1-(phenylthio)-2-aminopropane; D004299:Dopamine beta-Hydroxylase; D004298:Dopamine