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Halogen substitution of amphetamine-like drugs: Biochemical and pharmacological consequences
Frontiers in Catecholamine Research
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HALOGEN SUBSTITUTION OF AMPHETAMINE-LIKE DRUGS: BIOCHEMICAL AND PHARMACOLOGICAL CONSEQUENCES Fridolin Sulser and Elaine Sanders-Bush Department of Pharmacology, Vanderbilt University, School of Medicine, and Tennessee Neuropsychiatrie Institute, Nashville, Tennessee, U.S.A. An introduction of chlorine in the para position of the aromatic ring of amphetamine has pharmacological and biochemical consequences: 1. In s p e c i e s where p-hydroxylation of amphetamine is the major metabolic pathway, the biological half-life of the drug is increased 10-fold. Inhibition of the aromatic hydroxylase by iprindole (a t d c y c l i c antidepressant which does not block uptake of catecholamines) does not prolong the pharmacological action of p-chloroamphetamine but markedly enhances and prolongs that of amphetamine. Like p-hydroxyamphetamine, p-chloroamphetamine is, however, a substrate for /3-hydroxylase. 2. Although amphetamine and p-chloroamphetamine exert similar effects on r e l e a s e uptake and metabolism of brain catecholamines, p-chloroamphetamine has a higher affinity for the stores of catecholamines (.particularly dopamine) and its action appears not to depend on an intact synthesis of catecholamines. The psychomotor stimulation elicited by p-chloroamphetamine is not modified by the intraventricular injection of 6-hydroxydopamine, which causes destruction of noradrenergic neurons and a marked decrease of the activity of tyrosine hydroxylase in striatum and diencephalon. Reserpinization of animals whose noradrenergic neurons have been destroyed by 6ohydroxydopamine blocks the action of p-chloroamphetamine while that of amphetamine is not reduced. On the other hand, the action of amphetamine but not that of p-chloroamphetamine is s u s c e p t i b l e to tyrosine hydroxylase inhibition. 3. The in v i v o administration of p-chloroamphetamine causes a short lasting inhibition of the synaFtosomal uptake of catecholamines and a long lasting inhibition of the uptake of serotonin. 4. While both p-chloroamphetamine and amphetamine appear to increase the turnover of catecholamines (particularly dopamine) in brain, only p-chloroamphetamine d e c r e a s e s the rate of turnover of serotonin in brain. 5. Systemic administration of p-chloroamphetamine or the in vitro addition of p-chloroamphetamine (10 "~ to 10 ~M) does not change the activity of tyrosine hydroxylase in the striatum or in the diencephalon. In contrast to amphetamine, p-chloroamphetamine c a u s e s a marked and long-lasting inhibition of tryptophan hydroxylase in brain. This inhibition occurs only in vivo, is not apparent in
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Frontiers in Catecholamine Research
peripheral t i s s u e s and is a s s o c i a t e d with unchanged Km's of the enzyme for substrate or DMPH4. The long-lasting depletion of brain serotonin and 5-hydroxyindole acetic acid can, at l e a s t in part, be explained by the s e l e c t i v e inhibition of brain tryptophan hydroxylase. The decrease in the rate of turnover of brain serotonin can also be explained by inhibition of the rate limiting step in the s y n t h e s i s of brain serotonin. 6. The action of p-chloroamphetamine on adrenergic and serotonergic mechanisms thus differs markedly from that of amphetamine. Because of the observed temporal separation of the action of p-chloroamphetamine on central adrenergic (hours) and serotonergic mechanisms (weeks and even months), p-chloroamphetamine provides a new tool to study the physiological significance of aminergic s y s t e m s in brain.
MECHANISM OF or-ACTION IN THE ESTROGEN ~ I N A T E D GUINEA-PIG UTERUS Joseph H. Szurszewski Department of Physiology, Mayo Medical School, Rochester, Minnesota, U.S.A. The a-action of catecholamines on estrogen dominated guinea-pig uterus is stimulant. The response to norepinephrine falls into two categories. In the majority of preparations, norepinephrine depolarizes the membrane, reduces membrane resistance, a c c e l e r a t e s spontaneous spike discharge, and increases tension. In a few preparations, norepinephrine depolarizes the membrane, has either no or a slight measurable effect on membrane resistance and occasionally produces a few spontaneous spikes. Evidence obtained by modification of the external ionic environment indicates that the depolarization by norepinephrine is chloride dependent whereas the acceleration of the spontaneous spike discharge is sodium dependent. There are, however, several lines of evidence which suggest these effects might be preceded by an increase in free intracellular calcium. (1) Norepinephrine always produced an increase in the force of the phasic contraction. This positive inotropic response to norepinephrine occurred without a change in the evoked spike frequency, and it continued for several minutes after the administration of norepinephrine. It was observed in potassium-free solution, in sodium-free solution and was independent of the chloride mechanism, for it was also observed in chloridedeficient solution. It was abolished at temperatures below 32°C. (2) The depolarization and increase in conductance produced by norepinephrine was reduced when calcium was removed from the Krebs' solution and was abolished after adding EGTA. (3) Norepinephrine produced an increase in the resting tension in near isotonic potassium chloride solution, in chloride-deficient
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HALOGEN SUBSTITUTION OF AMPHETAMINE-LIKE DRUGS: BIOCHEMICAL AND PHARMACOLOGICAL CONSEQUENCES Fridolin Sulser and Elaine Sanders-Bush Department of Pharmacology, Vanderbilt University, School of Medicine, and Tennessee Neuropsychiatrie Institute, Nashville, Tennessee, U.S.A. An introduction of chlorine in the para position of the aromatic ring of amphetamine has pharmacological and biochemical consequences: 1. In s p e c i e s where p-hydroxylation of amphetamine is the major metabolic pathway, the biological half-life of the drug is increased 10-fold. Inhibition of the aromatic hydroxylase by iprindole (a t d c y c l i c antidepressant which does not block uptake of catecholamines) does not prolong the pharmacological action of p-chloroamphetamine but markedly enhances and prolongs that of amphetamine. Like p-hydroxyamphetamine, p-chloroamphetamine is, however, a substrate for /3-hydroxylase. 2. Although amphetamine and p-chloroamphetamine exert similar effects on r e l e a s e uptake and metabolism of brain catecholamines, p-chloroamphetamine has a higher affinity for the stores of catecholamines (.particularly dopamine) and its action appears not to depend on an intact synthesis of catecholamines. The psychomotor stimulation elicited by p-chloroamphetamine is not modified by the intraventricular injection of 6-hydroxydopamine, which causes destruction of noradrenergic neurons and a marked decrease of the activity of tyrosine hydroxylase in striatum and diencephalon. Reserpinization of animals whose noradrenergic neurons have been destroyed by 6ohydroxydopamine blocks the action of p-chloroamphetamine while that of amphetamine is not reduced. On the other hand, the action of amphetamine but not that of p-chloroamphetamine is s u s c e p t i b l e to tyrosine hydroxylase inhibition. 3. The in v i v o administration of p-chloroamphetamine causes a short lasting inhibition of the synaFtosomal uptake of catecholamines and a long lasting inhibition of the uptake of serotonin. 4. While both p-chloroamphetamine and amphetamine appear to increase the turnover of catecholamines (particularly dopamine) in brain, only p-chloroamphetamine d e c r e a s e s the rate of turnover of serotonin in brain. 5. Systemic administration of p-chloroamphetamine or the in vitro addition of p-chloroamphetamine (10 "~ to 10 ~M) does not change the activity of tyrosine hydroxylase in the striatum or in the diencephalon. In contrast to amphetamine, p-chloroamphetamine c a u s e s a marked and long-lasting inhibition of tryptophan hydroxylase in brain. This inhibition occurs only in vivo, is not apparent in
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Frontiers in Catecholamine Research
peripheral t i s s u e s and is a s s o c i a t e d with unchanged Km's of the enzyme for substrate or DMPH4. The long-lasting depletion of brain serotonin and 5-hydroxyindole acetic acid can, at l e a s t in part, be explained by the s e l e c t i v e inhibition of brain tryptophan hydroxylase. The decrease in the rate of turnover of brain serotonin can also be explained by inhibition of the rate limiting step in the s y n t h e s i s of brain serotonin. 6. The action of p-chloroamphetamine on adrenergic and serotonergic mechanisms thus differs markedly from that of amphetamine. Because of the observed temporal separation of the action of p-chloroamphetamine on central adrenergic (hours) and serotonergic mechanisms (weeks and even months), p-chloroamphetamine provides a new tool to study the physiological significance of aminergic s y s t e m s in brain.
MECHANISM OF or-ACTION IN THE ESTROGEN ~ I N A T E D GUINEA-PIG UTERUS Joseph H. Szurszewski Department of Physiology, Mayo Medical School, Rochester, Minnesota, U.S.A. The a-action of catecholamines on estrogen dominated guinea-pig uterus is stimulant. The response to norepinephrine falls into two categories. In the majority of preparations, norepinephrine depolarizes the membrane, reduces membrane resistance, a c c e l e r a t e s spontaneous spike discharge, and increases tension. In a few preparations, norepinephrine depolarizes the membrane, has either no or a slight measurable effect on membrane resistance and occasionally produces a few spontaneous spikes. Evidence obtained by modification of the external ionic environment indicates that the depolarization by norepinephrine is chloride dependent whereas the acceleration of the spontaneous spike discharge is sodium dependent. There are, however, several lines of evidence which suggest these effects might be preceded by an increase in free intracellular calcium. (1) Norepinephrine always produced an increase in the force of the phasic contraction. This positive inotropic response to norepinephrine occurred without a change in the evoked spike frequency, and it continued for several minutes after the administration of norepinephrine. It was observed in potassium-free solution, in sodium-free solution and was independent of the chloride mechanism, for it was also observed in chloridedeficient solution. It was abolished at temperatures below 32°C. (2) The depolarization and increase in conductance produced by norepinephrine was reduced when calcium was removed from the Krebs' solution and was abolished after adding EGTA. (3) Norepinephrine produced an increase in the resting tension in near isotonic potassium chloride solution, in chloride-deficient