- The Enantiomeric Specificity of the Antihypertensive Activity of 1-(Phenylthio)-2-aminopropane, a Synthetic Substrate Analogue for Dopamine β-Monooxygenase
-
We have found that (R,S)-1-(phenylthio)-2-aminopropane (4a), a synthetic alternate substrate for the terminal enzyme of norepinephrine biosynthesis, dopamine β-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, Heath H.,Husain, Philip A.,Colbert, James E.,Schweri, Margaret M.,Pollock, Stanley H.,et al.
-
p. 1082 - 1085
(2007/10/02)
-
- 2-(Arylthio)ethanamines and &α-(Arylthio)propionamides with Antidepressant Activity
-
Reaction of aziridine with thiophenols affords 2-arylthioethanamines; with 2-methylaziridine, ring opening occurs regiospecifically to provide 1-arylthio-2-propanamines.The structure of one member of this group, 1-(4-chlorophenylthio)-2-propanamine (7), has been proved by other unambiguous syntheses. 7 and isomer 12 arise from the alkylation of 4-chlorothiophenol with 2-chloropropylamine as well as from the displacement of the tosyl group in 1-(4-chlorophenylthio)-2-tosyloxypropane (13).Alkylation of 4-chlorothiophenol with α-chloropropionamide affords 11 which leads to 12 on LAH reduction.Ethanamines and propanamines are converted into guanidines, amides, ureas and thioureas.Many arylthioethanamines, e.g. 7, 22, 28, 38 and 39 (as HCl salts) and α-arylthiopropionamides, e.g. 11, 86, 91, 93 and 96 exhibit good activity in the DOPA potentiation and reserpine antagonism tests.Among these, 7 HCl is the most potent and does not inhibit rat brain MAO activity.In clinical trials, C 2998-Go compares favourably with imipramine.
- Nair, M. D.,David, J.,Nagarajan, K.
-
p. 940 - 947
(2007/10/02)
-