Methyldopa (α-methyl-3,4-dihydroxyphenyl-alanine), α-methyl- meta -tyrosine and their respective α-methyl-dihydroxyphenethylamines were demonstrated to be capable of antagonizing the cardiovascular actions of phenethylamine and amphetamine, but not norepinephrine, after appropriate pretreatment in dogs. In this respect the effects of these agents resembled those obtained with pretreatment with reserpine, syrosingopine and guanethidine. In contrast, these latter agents readily blocked the pressor response that occurs during stimulation of the central end of the vagus nerve whereas the α-methyl amino acids and amines were without effect.
The α-methyl amino acids produced a decrease in the concentration of catecholamines in the brain stem, heart and spleen after pretreatment, but not the adrenal gland in the pretreated dog. This action, except for the lack of effect on adrenal catecholamines, paralleled that reported for reserpine, syrosingopine and guanethidine in the dog and that reported for the amines derived from the a-methyl amino acids in other species. The ability of the α-methyl amino acids and amines to antagonize differentially the vascular effect of the sympathomimetic amines employed may be related to their ability to reduce the catecholamine content of some peripheral tissues. This latter effect, however, was not associated with disruption in transmission over sympathetic pathways since the pressor response occurring during stimulation of the central end of the vagus nerve was not reduced. The possible site and mechanism of action were discussed.
Journal Article Increased concentrations of 3-methoxy-4-hydroxyphenylethyleneglycol and homovanillic acid in rat brain after treatment with BE-2254 ("HEAT") Get access B V Clineschmidt, B V Clineschmidt Merck Institute for Therapeutic Research, West Point, Pennsylvania 19486, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar J A Totaro, J A Totaro Merck Institute for Therapeutic Research, West Point, Pennsylvania 19486, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar A B Pflueger, A B Pflueger Merck Institute for Therapeutic Research, West Point, Pennsylvania 19486, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar J C McGuffin J C McGuffin Merck Institute for Therapeutic Research, West Point, Pennsylvania 19486, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 27, Issue 10, October 1975, Pages 780–782, https://doi.org/10.1111/j.2042-7158.1975.tb09402.x Published: 12 April 2011 Article history Received: 24 April 1975 Published: 12 April 2011
The 3-hydroxy, 2,3- and 3,4-dihydroxy derivatives of DL-α-methylphenylalanine, and the corresponding derivatives of DL-α- methylphenethylamine, have been tested in the mouse for their ability to: 1) inhibit dopa decarboxylase, 2) influence the concentration of serotonin in the brain, and 3) influence the concentration of norepinephrine in the brain and heart.
The three amino acids were found to be decarboxylase inhibitors in vivo , the dihydroxy derivatives being more potent than the monohydroxy derivative. None of the amines in fluenced decarboxylation in vivo .
Brain serotonin concentrations were definitely decreased by the 3-hydroxy and 3,4-dihydroxy amino acids, maximum effects being noted about 3 hours following i.p. administration of the drugs, and return to normal levels observed by 16 hours post injection.
Measured 16 hours after drug administration, brain and heart norepinephrine was decreased by α-methyl-dopa, α-methyl-m-tyrosine and the corresponding amines with the exception that α-methyl-dopamine did not influence brain norepinephrine. In those cases where tissue norepinephrine was lowered, the effect was still discernible after 6 days.
The ability of α-methyl-dopa to inhibit dopa decarboxylase and deplete tissues of norepinephrine resides solely in the L-isomer.
(+/-)-CTC, a cyproheptadine derivative, possesses both antidopaminergic and anticholinergic activities which can be resolved, respectively, into its component (-)- and (+)-enantiomers. Both in vivo (antagonism of apomorphine-induced stereotypy, elevation of striatal homovanillic acid) and in vitro (inhibition of [3H]haloperidol binding), (-)-CTC was less active than haloperidol but more potent or equipotent compared to chlorpromazine. (+)-CTC was a more potent anticholinergic agent in vitro (inhibition of [3H]quinuclidinyl benzilate binding) than either thioridazine or clozapine, whereas in vivo (antagonism of the lethal action of physostigmine) the three compounds were similar. Comparison of the racemate with (-)-CTC in several in vivo test procedures to determine the influence of intrinsic anticholinergic activity showed that the presence of the anticholinergic (+)-enantiomer had little effect on the ability of (-)-CTC to antagonize apomorphine or elevate striatal homovanillic acid, whereas the activity of (-)-CTC was reduced in tests for postural asymmetry, avoidance and catalepsy. Stereoselectivity was also observed in terms of the alpha adrenergic blocking activity of CTC (inhibition of [3H]WB 4101 binding) which resides exclusively in the (-)-enantiomer. The ratios of (+)-CTC and (-)-CTC in terms of their anti-alpha adrenergic/antidopaminergic properties were large, suggesting a low propensity for the elicitation of orthostatic hypotension and sedation.
