Potent Noncompetitive Antagonist Research Articles

Electrophysiologically potent non-competitive glutamate antagonists at crayfish neuromuscular junctions are also potent inhibitors of [ 3H]MK801 binding to synaptic membranes from rat central nervous system

This paper describes effects of non-competitive glutamate antagonists, also known as “glutamate open channel blockers”, at crayfish neuromuscular junctions, on the binding of [ 3H]glutamate, [ 3H]CPP, [ 3H]AMPA, [ 3H]kainate and [ 3H]MK-801 to Triton-treated rat hippocampal synaptic membranes, and [ 3H]MK-801 to Triton-treated synaptic membranes from young rat spinal cord. The compounds tested were oxymatrine, theanine, diltiazem, chlorisondamine, tuberostemonine, trimethaphan, N 2- dansyl- L-arginine -4-t-butylpiperidi amide (TI 233), (1RS,2SR)-5-methyl-1-phenyl-2-(3-piperid-inopropyl amino) hexane-1-ol (MLV-5860) and (4S,5R)-4-(2-methylpropyl)-3-[3-(perhydroazepin-1-yl)propyl]-5-phenyl-1, 3-oxazoline-2-one (MLV-6976). Among compounds tested, MLV-5860, MLV-6976 and TI 233 potently inhibited the binding of [ 3H]MK-801 to Triton-treated rat hippocampal synaptic membranes, but not that of other 3H-labelled ligands. The inhibitory potency of MLV-6976 and MLV-5860 on the binding of [ 3H]MK-801 was similar to that of MK-801. MLV-6976 could also inhibit the inhibitory potency was similar to MK-801. These results suggest that potent glutamate antagonists, acting as open channel blockers at crayfish neuromuscular junction, may have similar pharmacological properties to MK-801 at the mammalian central nervous system, but the reverse may not always be true.

Homochiral structures derived from 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) are potent non-competitive antagonists of glutamate at NMDA receptor sites

The racemates of cis (pip/Me) 1-[1-(2-thienyl)-2-methylcyclohexyl]piperidine and cis (pip/Me) 1-[1-(2-furanyl)-2-methylcyclohexyl]piperidine, 2 derivatives of the noncompetitive N-methyl- d-aspartate (NMDA) antagonist 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) have been synthesized. The corresponding isomers were resolved by a crystallization procedure, via the diastereoisomeric salts formed with (+)- and (-)-di- O,O′-4-toluoyltartaric acid. The absolute configuration was determined by single-crystal X-ray analysis and by comparison with previously published data in related series. The 4 homochiral structures obtained were tested for their affinity for the PCP receptor sites labelled with [ 3H]TCP. Their neuroprotective potency was assessed in primary cultured neuronal cells against neurotoxicity induced by glutamate. The 2 (-)-1 S, 2 R-isomers displayed the highest affinity for the PCP receptor sites and the highest efficacy for neuronal protection in comparison with the (+)-1 R, 2 S-isomers.

Effects of NMDA receptor antagonists in squirrel monkeys trained to discriminate the competitive NMDA receptor antagonist NPC 12626 from saline

Because excitatory amino acids have been implicated in several physiological phenomena, antagonists of excitatory amino acid function may have significant therapeutic potential as anticonvulsant, neuroprotectants and anxiolytics. Drug discrimination procedures in animals have proven useful to compare and contrast the behavioral effects of site-selective NMDA antagonists. In the only previous study using a competitive NMDA antagonist as a training drug, rat wwere trained to discriminate NPC 12626 (2-amino-4,5(1,2-cyclohexyl)-7-phosphonoheptanoic acid) from nondrug. The major goal of the present study was to establish and characterize a nonhuman primate model of NPC 12626 discrimination. Adult male squirrel monkeys were trained to discriminate NPC 12626 from saline under a two-lever fixed ratio-30 schedule of food reinforcement. The monkeys required between 80 and 120 training sessions to acquire this discrimination after the training dose had been raised from 3 to 20 mg/kg i.m. The competitive NMDA antagonists CGP 37849 (D,L-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid) and CPPene (D-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid) substituted completely for NPC 12626, while the potent noncompetitive NMDA antagonist, dizocilpine (MK-801), did not. These results reflect a profile of discriminative stimulus effects which support that observed in rats and establish a primate model for use in further study of the behavioral effects of the competitive NMDA antagonists.

The NMDA receptor antagonist MK-801 elicits conditioned place preference in rats

(+)-5-Methyl-10,11-dihydro-5 H-dibenzo[ a, d]cyclohepten-5,10-imine maleate, (MK-801) a potent noncompetitive antagonist of central NMDA receptors, has been hypothesized to have rewarding properties indicative of abuse potential. To test this hypothesis, the effects of MK-801 on the acquisition of a conditioned place preference and on locomotor activity were assessed and compared with d-amphetamine. Both MK-801 (0.03 and 0.1 mg/kg, SC) and d-amphetamine (1.0 mg/kg, SC) administration resulted in the acquisition of a conditioned place preference. However, while both amphetamine and the higher dose of MK-801 produced a behavioral activation during the training period the lower dose of MK-801 did not. These results suggest that MK-801, at doses that produce behavioral activation and below, is rewarding and therefore may have abuse potential.

Ketamine-induced anesthesia involves the [formula omitted] receptor-channel complex in mice

The role of the N- methyl- d-aspartate (NMDA) receptor-channel complex in ketamine-induced anesthesia was examined in mice. General anesthetic potencies were evaluated on a rating scale, which provided the data for anesthetic scores, loss of righting reflex, sleeping time and recovery time. All drugs were administered intraperitoneally. NMDA (60–300 mg/kg), an NMDA receptor agonist, dose-dependently antagonized the general anesthetic potencies of ketamine at a dose of 100 mg/kg which produced loss of righting reflex in more than 90% of the mice. On the other hand, a high dose of N- methyl- l-aspartate (400 mg/kg), a stereoisomer of NMDA, did not. A dose of 300 mg/kg of NMDA significantly shifted the dose-response curve of ketamine for loss of righting reflex to the right. A high dose of d-cycloserine (200 mg/kg), an agonist at the glycine site on the NMDA receptor complex, slightly but significantly shortened the sleeping time caused by ketamine (100 mg/kg). However, neither a critical subconvulsive dose of kainate (15 mg/kg), a kainate receptor agonist, nor a subsconvulsive dose of quisqualate (120 mg/kg), an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor agonist, reversed general anesthesia induced by 100 mg/kg of ketamine. Both the competitive NMDA antagonist, (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP; 10–30 mg/kg), and the non-competitive NMDA antagonist, MgCl 2 (30–120 mg/kg), dose-dependently potentiated the anesthetic actions induced by a lower dose of ketamine (70 mg/kg) which produced loss of righting reflex in less than 20% of the mice, but (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine hydrogen maleate (MK-801; 0.3–3.0 mg/kg), another potent non-competitive NMDA antagonist, did not. However, pretreatment with a low dose of haloperidol (0.1 mg/kg), a dopamine receptor antagonist, along with 0.3 mg/kg of MK-801 (which in itself elicited only stimulant actions), significantly increased the anesthetic potencies of ketamine at 70 mg/kg. Pharmacokinetic studies revealed that NMDA (300 mg/kg) and CPP (30 mg/kg) did not significantly alter the level of ketamine in the brain. These results suggest that ketamine-induced anesthesia is mediated, at least in part, by the NMDA receptor-channel complex.

Anesthesia and Muscle Relaxation with Intrathecal Injections of AR636 and AG489, Two Acylpolyamine Spider Toxins, in Rat

Acylpolyamine toxins are constituents isolated from many invertebrate predator venoms. These toxins are structurally novel and potent noncompetitive ligand-mediated ion channel antagonists. This study was designed to explore the sensory and motor effects of intrathecally applied acylpolyamine toxin. AR636 and AG489, acylpolyamine toxins from the spiders Argiope aurantia and Agelenopsis aperta, respectively, were injected intrathecally into rats prepared with chronic spinal catheters, and the effect on spinal function was assessed. AR636 was found to evoke a dose-dependent incidence of muscle flaccidity as well as a blockade of the agitation otherwise evoked by noxious mechanical and thermal stimuli applied to the tail or hind paws. AR636 has a calculated effective concentration (EC50) of 2 micrograms for motor inhibition and 7 micrograms for sensory inhibition. In contrast, AG489 was not found to have any effects at the highest tested dose of 50 micrograms. The precise mechanism whereby AR636 exerts its action in the rat spinal cord is not known, but in insect models, this agent is known to act as a postsynaptic, noncompetitive antagonist at a glutamate receptor and to block cholinergic-gated ion channels. Thus, this agent, a representative of the acylpolyamine toxins, has prominent effects on the sensory and motor systems of mammals, and this class of agents may be found to have potential application as spinally acting muscle relaxants and/or anesthetics.

BQ-123, cyclo(-D-Trp-D-Asp-Pro-D-Val-Leu), is a non-competitive antagonist of the actions of endothelin-1 in SK-N-MC human neuroblastoma cells

SK-N-MC cells, derived from a human neuroblastoma, respond to endothelin (ET) peptides with an increase in the free intracellular calcium concentration. The response is biphasic, with the secondary plateau phase being abolished or reduced by removal of extracellular Ca2+ or by the presence of 100nM nitrendipine. Restoration of Ca2+ to the bathing solution in cells stimulated by ET-1 in the absence of Ca2+ caused the plateau to reappear. The order of potency of ET family peptides was ET-2≥sarafotoxin S6b≥ET-1≫ET-3, suggesting that ETA receptors mediate the response. Sarafotoxin S6c and the C-terminal hexapeptide endothelin (16–21) were inactive in these cells. [Ala1,3,11,15]ET-1, a linear analogue of ET-1 which has been suggested to be a selective ETB receptor agonist, was a weak competitive antagonist of the actions of ET-1 in these cells. However, BQ-123, recently introduced as a selective and competitive antagonist at ETA receptors, was a potent non-competitive antagonist of ET-1 giving a 50% reduction in the maximum response at 6nM.

Influence of MK-801 on the anticonvulsant activity of antiepileptics

MK-801 (a potent non-competitive antagonist of N-methyl-D-aspartic acid-mediated events) in subcutanteous doses of 0.1 and 0.2 mg/kg increased the threshold for electroconvulsions and in doses of 0.0031 and 0.0125 mg/kg enhanced the protective activity of valproate against maximal electroshock-induced convulsions in mice. Valproate-induced side-effects (evaluated by means of dark-avoidance acquisition and retention testing and the chimney test) at its ED 50, against maximal electroshock (i.e. 268 mg/kg) were pronounced whereas they were absent in the case of a combined treatment with MK-801 (0.0125 mg/kg) and valproate (91 mg/kg). This treatment provided 50% protection against maximal electroshock-induced seizures. Moreover. MK-801 (0.0125 and 0.05 mg/kg) potentiated the anticonvulsant action of phenobarbital, reducing phenobarbital-induced motor impairment totally at 0.05 mg/kg, but did not influence the protection offered by carbamazepine and diphenylhydantoin at 0.05 mg/kg. The N-methyl-D-aspartic acid antagonist did not affect the total plasma levels of either valproate or phenobarbital (as measured by immunofluorescence), so a pharmacokinetic interaction, in terms of total plasma levels at least, is unlikely to be involved in the observed effects. The finding that the combined treatment of MK-801 with valproate or phenobarbital, apart from the distinct potentiation of their anticonvulsant activities, is devoid of side-effects should be carefully considered.

N-methyl- d-aspartate receptors mediate dopamone-induced changes in extrapyramidal and limbic dynorphin systems

The N-methyl- d-aspartate (NMDA)-type glutamate receptor was shown to mediate dopamine-induced dynorphin A (Dyn) changes in extrapyramidal and limbic structures. MK801, a potent noncompetitive antagonist of the NMDA receptor, blocked increases in striatal and nigral Dyn content following single and multiple administrations of methamphetamine (METH). Significant attenuation of the METH-induced increases occured with MK801 doses of 0.1 mg/kg/dose with complete blockade at 2.5 mg/kg/dose. Similar METH, NMDA itself caused significant increases in striatal and nigral Dyn content. The NMDA-induced increase in striatal Dyn content was blocked by coadministration of an intermediate dose of MK801. The Dyn system associated with the nucleus accumbens responded in a similar manner in that MK801 totally blocked the METH-induced increases; moreover, NMDA elevated the Dyn content in this structure. The inability of MK801 to alter the quinpirole-induced decrease in striatal Dyn content suggests that the NMDA receptor is not involved in the D 2 receptor regulation of striatal Dyn systems.

Endogenous Excitatory Amino Acid Involvement in the Preovulatory and Steroid-Induced Surge of Gonadotropins in the Female Rat*

The physiological role of N-methyl-D-aspartate (NMDA) receptors in the regulation of preovulatory and steroid-induced surges of gonadotropins in the female rat was examined. The specific and potent noncompetitive NMDA receptor antagonist MK801 was used for blockade of NMDA neurotransmission. MK801 treatment completely inhibited the ability of progesterone to induce LH and FSH surges in the estrogen-primed ovariectomized rat. Administration of MK801 on proestrus in the immature female rat primed with PMSG resulted in a significant attenuation of the proestrous LH, FSH, and PRL surge and a corresponding attenuation of ovulation. Similarly, in the adult cycling female rat, MK801 administration on proestrus led to a significant attenuation of the proestrous LH and PRL surges. Mean FSH levels were lower in MK801-treated adult rats than in vehicle-treated rats, but this effect was not significant. In the estrogen-primed ovariectomized immature rat, the agonist NMDA caused a rapid (less than 10 min) elevation of LH and FSH in vivo. The gonadotropin-releasing effect of NMDA may be mediated at the level of the hypothalamus, since the medial basal hypothalamus/preoptic area of NMDA-treated rats killed 3 and 5 min post-NMDA had a significantly greater release of GnRH in vitro than that of vehicle-treated rats. In conclusion, these findings demonstrate that the preovulatory gonadotropin surge in the female rat is dependent on NMDA neurotransmission for its expression and add further evidence for a critically important role for NMDA receptors in the physiological regulation of gonadotropin secretion in the female rat.

Selective antagonism of calcium channel activators by fluspirilene

1. Fluspirilene has been claimed to bind to a high affinity site in the calcium channel in skeletal muscle. We have investigated its calcium-antagonistic effects in smooth muscle and affinity for the channel in radioligand binding assays. 2. Fluspirilene was weakly active as an antagonist of Ca2(+)-induced contractions in K(+)-depolarized taenia preparations from the guinea-pig caecum, with threshold antagonism starting from concentrations of 30 nM. Nitrendipine, nicardipine and nimodipine were very potent antagonists in this model (threshold antagonism, greater than 1 nM). 3. In contrast, fluspirilene (10-1000 nM) was a potent non-competitive antagonist of the effects of Bay K 8644 (1-3000 nM) on Ca2(+)-induced contractions and, at 10 nM, selectively antagonised the effects of Bay K 8644, abolished the Ca2(+)-channel activator effects of CGP 28392, without changing the calcium antagonist effects of nitrendipine, or modifying the sensitivity of the tissues to Ca2+. In contrast, the dihydropyridines were more effective as antagonists of Ca2+ than of Bay K 8644. Fluspirilene therefore selectively antagonised the effects of dihydropyridine Ca2+ channel activators without affecting the antagonist potency. 4. In radioligand binding experiments, fluspirilene was a potent displacer of [3H]-PN-200-110 binding to rat cerebral cortical membranes (EC50 30 nM), albeit with a low Hill slope (0.66), and was more potent than other lipophilic diphenylalkylamines such as flunarizine and lidoflazine. Fluspirilene interacted non-competitively with [3H]-PN-200-110 and increased dissociation of the radioligand.

The effect of MK-801 on the micturition reflex in anesthetized rats

We studied the effect of MK-801, a potent non-competitive NMDA receptor antagonist, on the micturition reflex in anesthetized rats. Pretreatment with MK-801 (0.1–1 mg/kg i.v.) dose dependently increased the bladder capacity and reduced the micturition contraction. The ability of MK-801 to inhibit bladder voiding was confirmed in additional experiments in which the compound (30–50 μg/kg i.v.) transiently suppressed established bladder voiding produced by continuous bladder filling. MK-801 (1 μM) did not affect nerve-mediated contractions of the rat bladder or inhibit the response to capsaicin. These findings provide pharmacological evidence for an involvement of NMDA receptors in the micturition reflex pathways.

Regional Neuroprotective Effects of the NMDA Receptor Antagonist MK-801 (Dizocilpine) in Hypoglycemic Brain Damage

Current evidence points to an important role of N-methyl-D-aspartate (NMDA) receptor activation in the pathogenesis of hypoglycemic neuronal death. MK-801 [dizocilpine maleate, (+)-5-methyl-10,11-dihydro-5H-di[a,d]cyclohepten-5,10-imine] is an anticonvulsant compound also known to be a potent noncompetitive antagonist at NMDA receptors, readily crossing the blood-brain barrier after parenteral administration. Treatment of rats with dizocilpine (1.5-5.0 mg/kg) injected intravenously during profound hypoglycemia (blood glucose levels 1.5-2.0 mM) at the stage of delta-wave (1-4 Hz) slowing of the EEG mitigated selective neuronal necrosis in the hippocampus and striatum, assessed histologically after 1-week survival. The degree of neuroprotection in the striatum and in the CA1 pyramidal cells of the hippocampus was dose dependent. Because of concern for a possible hypothermic mechanism of brain protection by MK-801, core temperature was closely monitored and was found not to decrease significantly. Since CBF is normal or increased in hypoglycemia, a fall in brain temperature during hypoglycemia is unlikely to play a role in the mechanism of the neuroprotection seen with the drug. The findings indicate that in profound hypoglycemia, intravenous administration of the NMDA antagonist dizocilpine, even after the appearance of delta-wave EEG slowing, can reduce the number of necrotic neurons in several brain regions and suggest that the neuroprotective effect of MK-801 is not related to hypothermia.

The NMDA antagonist MK-801 improved metabolic recovery after 10 minutes global cerebral ischaemia in rats measured with 31 phosphorous magnetic resonance spectroscopy

The blockade of postsynaptic receptors for excitatory amino acids is a promising new field for the possible treatment of cerebral ischaemia. The most important receptor seems to be the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptors and MK-801 is a potent non-competitive antagonist to the NMDA receptor. 31P NMR Spectroscopy was used to measure the recovery of intracellular pH and the high energy phosphates Phosphocreatine (PCr) and ATP after ten minutes of temporary global cerebral ischaemia in the rat. Cerebral ischaemia was obtained by combining bilateral carotid ligation and systemic hypotension (2 vessel occlusion model). Two intervention groups with intravenous injection of MK-801 in doses of 0.25 mg/kg and 0.5 mg/kg 15 minutes before onset of ischaemia were compared to a control group. Both intervention groups showed a more rapid recovery of PCr and ATP than the control group, but there were no significant differences for intracellular pH.

The topography of MK-801-induced locomotor patterns in rats

Locomotor patterns in rats given systemic injections of the novel, noncompetitive N-methyl-D-aspartate (NMDA) antagonist, MK-801 were characterized using Digiscan Animal Activity Monitoring System. At low systemic doses, MK-801 produced an activity pattern most similar to patterns previously described for less potent noncompetitive NMDA antagonists; this was typified by hyperactive locomotor behavior, with increases in distance travelled, speed, and clockwise/anticlockwise locomotion, and a marked decrease in rearing behavior. Although MK-801 elicited some motor patterns similar to those previously described for sympathomimetic agents, including hyperactivity and increased stereotypy, it did not produce increased rearing behavior, the most prominent sympathomimetic effect. These results demonstrated that the topography of locomotion elicited by low systemic doses of MK-801 is most similar to locomotor patterns previously described for noncompetitive NMDA receptor antagonists.

Pre- and post-ischemic administration of dizocilpine (MK-801) reduces cerebral necrosis in the rat.

The purpose of this study was to determine the effectiveness of the non-competitive N-methyl-D-aspartate receptor antagonist dizocilpine, or (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801) in mitigating ischemic neuronal necrosis in the rat. Ten minutes of transient forebrain ischemia was induced by a combination of bilateral carotid clamping and hypotension to 50 mm Hg. Control animals received intravenous saline, whereas treated animals received dizocilpine, either 1 mg/kg iv 20 min. pre ischemia, 1 mg/kg iv 20 min. post ischemia, 10 mg/kg iv 20 min. post ischemia, 10 mg/kg ip 2 hrs. post ischemia, 10 mg/kg ip 24 hrs. post ischemia. The groups receiving dizocilpine before or up to 20 min. after ischemia all showed a significant reduction in the number of dead neurons as assessed by quantitative histopathology in hippocampus, caudate nucleus and cerebral cortex after one week of recovery. However, dizocilpine administered either 2 or 24 hrs. after ischemia afforded no protection. These results suggest that the potent non-competitive NMDA antagonist dizocilpine may have some value in protecting the brain from hippocampal and cortical neuronal necrosis after a short insult consisting of dense transient cerebral ischemia. Noteworthy is the fact that pharmacologic intervention in the post-ischemic period was successful in preventing neuronal death, provided that drug administration occurred within dizocilpine's "therapeutic window".

Regulation of NMDA receptor desensitization in mouse hippocampal neurons by glycine

Responses to the excitatory amino acid N-methyl-D-aspartate (NMDA) are markedly potentiated by nanomolar concentrations of glycine. This is due to the action of glycine at a novel strychnine-resistant binding site with an anatomical distribution identical to that for NMDA receptors, suggesting that the NMDA receptor channel complex contains at least two classes of amino-acid recognition site. Antagonists at the glycine-binding site associated with NMDA receptors act as potent non-competitive antagonists, but do not alter the mean open time or conductance, as estimated by fluctuation analysis. The mechanisms by which glycine acts on NMDA receptors are unknown, but single-channel recording experiments show an increase in opening frequency with no change in mean open time or conductance, suggesting that glycine could regulate transitions to states that are intermediate between binding of NMDA receptor agonists and ion-channel gating. It has been suggested that glycine acts as a co-agonist at the NMDA receptor, and that responses to NMDA cannot be obtained in the complete absence of glycine, but in these experiments the response to NMDA was measured at equilibrium, and it is unlikely that sufficient temporal resolution was achieved to detect rapid alterations in receptor gating. Using a fast perfusion system we find that glycine regulates desensitization at NMDA receptors; this has a major effect on the response to NMDA measured at equilibrium, as would occur with slower applications of agonist. Reduction of NMDA receptor desensitization by glycine provides an example of a novel mechanism for regulation of ion-channel activity.

The effect of MK-801 and other antagonists of NMDA-type glutamate receptors on brain-stimulation reward

MK-801 is a ligand at phencyclidine recognition sites associated with NMDA-coupled cation channels, where it acts as a potent noncompetitive antagonist of central glutamate/aspartate (NMDA-type) receptors. Low doses (10-100 micrograms/kg IP) produced a dose-related and prolonged (greater than 1 h) enhancement of variable-interval self-stimulation responding. Higher doses (300 micrograms/kg) caused flaccid ataxia and disrupted responding. Ketamine HCl (3.0-100 mg/kg IP), a dissociative anaesthetic binding to the phencyclidine site, produced a similar response pattern, but facilitation was less prolonged and occurred over a narrower dose range. Kynurenic acid (3.0-300 mg/kg IP), a nonselective competitive antagonist of glutamate receptors, produced only depression of responding, possibly the result of kynurenate-induced blockade of central kainate and/or quisqualate receptors. The behavioural stimulant effects of MK-801 appear to be an intrinsic and essential feature of selective NMDA antagonists, and these effects of MK-801 differ qualitatively and quantitatively from the well-known facilitatory effects of dopamine-dependent stimulants.

Inhibition of tryptophan pyrrolase by serotonin, epinephrine and tryptophan analogs

Many tryptophan analogs were found to effectively block the conversion of tryptophan to kynurenine in the tryptophan pyrrolase reaction. Side-chain variants such as indole-3-acrylic acid were competitive inhibitors of tryptophan. Substitution of the indole ring produced several noncompetitive inhibitors, of which serotonin was the most effective. Epinephrine and certain other phenols were also potent noncompetitive antagonists. The inhibition by epinephrine and other phenols may be due to interaction at the heme site for this enzyme. None of the inhibitors tested induced tryptophan pyrrolase in the adrenalectomized rat when administered in vivo.