Poor Brain Penetration Research Articles

Research and Development of Donepezil Hydrochloride, a New Type of Acetylcholinesterase Inhibitor

A wide range of evidence shows that Cholinesterase (ChE) inhibitors can interfere with the progression of Alzheimer’s disease (AD). The earliest known ChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of AD patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters, while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase (AChE) inhibitor that would overcome the disadvantages of these two compounds. During the study, by chance we found a seed compound. We then conducted a structure-activity relationship study of this compound. After four years of exploratory research, we found donepezil hydrochloride (donepezil). Donepezil showed several positive characteristics including the following: 1) It has a novel structure compared to other conventional ChE inhibitors; 2) It shows strong anti-AChE activity and has long lasting efficacy; 3) The inhibitory characteristic of donepezil shows that it is highly selective for AChE as compared to butyryl-cholinesterase (BuChE) and showed reversibility; 4) The results of clinical studies on donepezil show a very high significant difference on ADAS cog and CIBIC plus scores of AD patients. Donepezil is currently marketed in 56 countries all over the world.

Carbon-11 labelled cholecystokinin B antagonists : Radiosynthesis and evaluation in rats

Three cholecystokinin type B (CCK b) receptor antagonists were labelled with 11C and evaluated ex vivo in rat biodistribution studies. The CCK b antagonists were YF 476 and two other compounds of the basic 3-ureido-1,4-benzodiazepine class. Following tail-vein administration of [ 11C]-YF 476 exceedingly low levels of radioactivity were found in all brain regions from 5 to 60 min post-injection. Similar results were obtained using the other two 11C-labelled CCK b antagonists. In light of the very poor brain penetration of these compounds, reports on the central nervous system activity of this class of CCK b antagonists should be viewed with caution.

Donepezil hydrochloride: a treatment drug for Alzheimer's disease.

The role of the cholinergic system with respect to cognitive deficits characteristic of Alzheimer's disease (AD) has led to a number of studies focusing on the development of acetylcholinesterase (AChE) inhibitors as a drug for treating this disease. The earliest known AChE inhibitors, namely, physostigmine and tacrine, performed poorly in clinical trials (e.g., poor oral activity, brain penetration, and hepatotoxic liability). Studies were then focused on finding a new type of acetylcholinesterase inhibitor that would overcome the disadvantages of these two compounds. Donepezil hydrochloride inaugurates a new class of AChE inhibitors with longer and more selective action and with manageable adverse effects.

Rediscovering good old friend IGF-I in the new millenium: possible usefulness in Alzheimer's disease and stroke

Much research has been done over the past two decades on the role of insulin-like growth factors I and II (IGF) in the maintenance of normal body homeostasis, especially in regard to various endocrine functions, growth and aging. For example, IGF-I is a well established promoter of tissue growth and has been used in the clinics for the treatment of growth related disorders, even being abused by athletes to enhance performance in competitions. In contrast, comparatively limited attention has been given to the potential significance of the IGFs in the central nervous system. Over the past few years, we have studied the trophic as well as neuromodulatory roles of the IGFs in the brain. IGF-I and IGF-II are potent modulators of acetylcholine release; IGF-I inhibiting release while IGF-II is a potent stimulant. Moreover, only the internalization of the IGF-I receptor complex was blocked by an inhibitor of phosphotyrosylation. This is in accordance with the differential nature of the IGF-I and IGF-II receptors, the former being a tyrosine kinase receptor while the later is a single transmembrane domain protein bearing binding sites for 6-mannose phosphate containing residues. The activation of IGF-I receptors protected neurons against cell death induced by amyloidogenic derivatives likely by an intracellular mechanism distinct from those involved in the regulation of acetylcholine release and neuronal growth. The stimulation of IGF-I receptors can activate intracellular pathways implicating a PI3/Akt kinase and CREB phosphorylation or modulate the production of free radicals. The effects, particularly those of IGF-I on key markers of the Alzheimer's (AD) brains namely cholinergic dysfunction, neuronal amyloid toxicity, tau phosphorylation and glucose metabolism suggest the potential usefulness of this growth factor in the treatment of neurodegenerative diseases. However, the poor bioavailability, enzymatic stability and brain penetration of IGF-I hamper progress in this regard. The recent development of a small, non-peptidyl mimetic of insulin able to directly activate the insulin receptor [Zhang, B., Salituro, G., Szalkowski, D., Li, Z., Zhang, Y., Royo, I., Vilella, D., Diez, M.T., Pelaez, F., Ruby, C., Kendall, R.L., Mao, X., Griffin, P., Calaycay, J., Zierath, J.R., Heck, J. V., Smith, R.G., Moller, D.E., 1999. Science, 284, 974–977] suggests that a similar strategy could be used for IGF-I and the IGF-I receptor leading to the characterization of IGF-I mimics of potential clinical usefulness.

Donepezil hydrochloride (E2020) and other acetylcholinesterase inhibitors.

A wide range of evidence shows that acetylcholinesterase (AChE) inhibitors can interfere with the progression of Alzheimer's disease (AD). The successful development of these compounds was based on a well-accepted theory that the decline in cognitive and mental functions associated with AD is related to the loss of cortical cholinergic neurotransmission. The earliest known AChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of Alzheimer's patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase inhibitor that would overcome the disadvantages of these two compounds. Donepezil hydrochloride inaugurates a new class of AChE inhibitors with longer and more selective action with manageable adverse effects. Currently, there are about 19 new Alzheimer's drugs in various phases of clinical development.

Structure-activity relationships of acetylcholinesterase inhibitors: Donepezil hydrochloride for the treatment of Alzheimer’s Disease

Abstract

Why are non‐sedating antihistamines non‐sedating?

In this paper several factors which may influence the potential of a certain antihistamine to cause CNS‐related side‐effects are discussed. It is shown by pharmacological studies that the H1 receptors occurring in CNS tissue or in peripheral organs do not differ with regard to their affinity for H1 blockers. There is also no other evidence for subtypes of the H1 receptor. The sedating properties are caused by H1 blockade. The level of brain penetration (passage of the blood–brain barrier) is not fully determined by the lipophilicity (log P) of an individual compound. Compounds with a low or a high lipophilicity (log P) do not penetrate. For compounds with a basic centre the log D should be applied, replacing the log P; the log D corrects for the level of ionization of such compounds, as neutral species only readily enter into the CNS. For compounds with an intermediate log P or log D a Δlog P is introduced; a Δlog P indicates a large hydrogen binding capacity. A strong hydrogen binding capacity means a strong (serum) protein binding and consequently a poor brain penetration. Also the role of the P‐glycoprotein as a transporter out of the CNS is introduced. Finally the influence of histamine on the permeability of the blood–brain barrier is discussed; it is shown that histamine increases the extravasation of, for example, albumin.

Alprazolam and lorazepam: Differential tolerance development to the adverse memory effects in the elderly

Animals or human subjects receiving brain stimulation in the dorsal periaqueductal gray matter (dPAG) show sudden fear-suggestive behavioral reactions and physical signs of autonomic activation which are reminiscent of the symptom profile characterizing a panic attack. An experimental situation in rats measuring dPAG stimulation self-interruption thresholds has been validated as realistically simulating several aspects of panic anxiety with objective signs of symptomatic and predictive validity using established antipanic and panicogenic agents; it was utilized here to evaluate the effects of various cholecystokinin B receptor ligands. A dose-dependent increase in self-interruption thresholds (antipanic-like effect) was recorded following injection of L-365,260 (3.2, 10 and 32 mg/kg i.p.), a CCKB receptor antagonist with good brain penetration, whereas no significant changes in thresholds were recorded following CI-988 (3.2, 10 and 32 mg/kg i.p.), a dipeptoid CCKB receptor antagonist with poor brain penetration. Latencies for self-interruption were not modified, suggesting that motor functions remained intact. No significant changes in self-interruption thresholds were recorded following peripheral administration of the CCKB receptor agonists CCK4 (0.03 to 0.32 mg/kg i.v.; 0.01 to 3.2 mg/kg i.p.) or the metabolically stabilized analog Boc-CCK4 (0.1 to 10 mg/kg i.p.). Systemic administration of the panicogenic compounds caffeine and yohimbine enhance acute anxiety in this model. These data indicate that, in the dPAG simulation of panic anxiety, central CCKB receptor blockade by L-365,260 induces antiaversive effects analogous to those observed following benzodiazepine receptor activation by clonazepam or alprazolam. Potency and efficacy of L-365,260 were lower than those of clonazepam or alprazolam, suggesting modest, but nonetheless authentic, antiaversive properties for this CCKB receptor antagonist. Lack of effects observed following peripheral administration of the agonists CCK4 and Boc-CCK4 or of the dipeptoid antagonist CI-988 is likely to reflect restricted brain penetration of those compounds in rats; it furthermore excludes a contribution of peripheral gastrin and CCKA receptors to the antipanic-like properties of selective CCKB receptor antagonists such as L-365,260.

Behavioral effects of CCK B receptor ligands in a validated simulation of panic anxiety in rats

Animals or human subjects receiving brain stimulation in the dorsal periaqueductal gray matter (dPAG) show sudden fear-suggestive behavioral reactions and physical signs of autonomic activation which are reminiscent of the symptom profile characterizing a panic attack. An experimental situation in rats measuring dPAG stimulation self-interruption thresholds has been validated as realistically simulating several aspects of panic anxiety with objective signs of symptomatic and predictive validity using established antipanic and panicogenic agents; it was utilized here to evaluate the effects of various cholecystokinin B receptor ligands. A dose-dependent increase in self-interruption thresholds (antipanic-like effect) was recorded following injection of L-365,260 (3.2, 10 and 32 mg/kg i.p.), a CCK B receptor antagonist with good brain penetration, whereas no significant changes in thresholds were recorded following CI-988 (3.2, 10 and 32 mg/kg i.p.), a dipeptoid CCK B receptor antagonist with poor brain penetration. Latencies for self-interruption were not modified, suggesting that motor functions remained intact. No significant changes in self-interruption thresholds were recorded following peripheral administration of the CCK B receptor agonists CCK 4 (0.03 to 0.32 mg/kg i.v.; 0.01 to 3.2 mg/kg i.p.) or the metabolically stabilized analog Boc-CCK 4 (0.1 to 10 mg/kg i.p.). Systemic administration of the panicogenic compounds caffeine and yohimbine enhance acute anxiety in this model. These data indicate that, in the dPAG simulation of panic anxiety, central CCK B receptor blockade by L-365,260 induces antiaversive effects analogous to those observed following benzodiazepine receptor activation by clonazepam or alprazolam. Potency and efficacy of L-365,260 were lower than those of clonazepam or alprazolam, suggesting modest, but nonetheless authentic, antiaversive properties for this CCK B receptor antagonist. Lack of effects observed following peripheral administration of the agonists CCK 4 and Boc-CCK 4 or of the dipeptoid antagonist CI-988 is likely to reflect restricted brain penetration of those compounds in rats; it furthermore excludes a contribution of peripheral gastrin and CCK A receptors to the antipanic-like properties of selective CCK B receptor antagonists such as L-365,260.

Brain perfusion systems for studies of drug uptake and metabolism in the central nervous system.

Recent advances in biotechnology and the pharmaceutical sciences have greatly expanded the number of drugs that are being developed for the treatment of central nervous system (CNS) diseases. These drugs include a wide array of antibody, protein, peptide, and recombinant DNA agents as well as novel small agents (e. g., amino acids, nucleic acid precursors, and receptor agonists or blockers) for the treatment of brain tumors, strokes, infections, and neurodegenerative diseases. Though such agents often show excellent activity in vitro, many exhibit only restricted activity in vivo because of poor brain uptake and penetration. This problem has stimulated new work on factors that control drug uptake into brain and on methods to enhance CNS drug delivery.

5-HT1D receptor agonist properties of novel 2-[5-[[(trifluoromethyl)sulfonyl]oxy]indolyl]ethylamines and their use as synthetic intermediates.

2-[5-[[(trifluoromethyl)sulfonyl]oxy]-1H-indol-3-yl]ethylamine (18), its N,N-di-n-propyl (12), N,N-diethyl (13), and N,N-dimethyl (14) derivatives, and 4-[3-[2-(N,N-dimethylamino)ethyl]-1H-indol-3-yl]-N-(p-methoxybenzyl) acrylamide (GR46611, 19) were synthesized and tested for binding affinities to cloned 5-HT1A, 5-HT1D alpha, 5-HT1D beta, and D2 receptors. In addition, the intrinsic efficacy was measured as the reduction of forskolin-stimulated cAMP in cells transfected with 5-HT1D alpha and 5-HT1D beta receptors in vitro. The 5-substituted indolyethylamines investigated displayed agonist activity at the 5-HT1D receptors with varying degrees of preference for the 5-HT1D alpha vs the 5-HT1D beta receptors. The primary amine and N,N-dimethyl substitution seemed to be optimal for 5-HT1D alpha affinity. Furthermore, the N,N-diethyl (13) and N,N-dimethyl (14) derivatives showed a 10-25 times preference for the 5-HT1D alpha vs the 5-HT1D beta receptor. In addition, all of the novel compounds showed affinity for the 5-HT1A receptor in vitro (Ki values ranging from 18 to 40 nM). The most promising derivative 14 was virtually devoid of central 5-HT1A agonist activity in rats, as determined by in vivo biochemical assays. Paradoxically, 14, like 19, induced a hypothermic response and a decrease in 5-HIAA levels in the prefrontal cortex and hypothalamus in guinea pigs after systemic administration. Sumatriptan failed to produce either of these effects due to a poor brain penetration.

Alpha 1-adrenoceptor antagonists differentially control serotonin release in the hippocampus and striatum: a microdialysis study.

Using the in vivo microdialysis technique, we have studied the effect of the systemic administration of several alpha 1-adrenoceptor antagonists on the extracellular levels of serotonin (5-HT) in the rat hippocampus. Prazosin, and to a lesser extent, terazosin, decreased these levels by 50-65% for 0.03-0.4 mg/kg, i.v. and by 30-40% for 0.1-0.4 mg/kg, i.v., respectively. In contrast, alfuzosin, an alpha 1-adrenoceptor antagonist with poor brain penetration, did not significantly affect these levels even at the high dose of 0.4 mg/kg, i.v. When perfused into the hippocampus through the dialysis probe, prazosin (1-10 microM) induced a more limited (20-30%) and delayed decrease in 5-HT outflow. These results support the existence of a central noradrenergic facilitatory influence, mediated by alpha 1-adrenoceptors, on serotonergic neurons projecting to the hippocampus. In the striatum prazosin (0.4 mg/kg, i.v.) decreased 5-HT levels to a smaller extent (-35%) than in the hippocampus (-65%), suggesting the existence of differences in the degree of noradrenergic influence on median and dorsal raphé nuclei, which preferentially project to the hippocampus and striatum, respectively.

Anticonvulsant activity of antagonists and partial agonists for the NMDA receptor-associated glycine site in the kindling model of epilepsy

Several previous studies have shown that competitive and uncompetitive N-methyl- d-aspartate (NMDA) receptor antagonists are ineffective as anticonvulsants in fully amygdala kindled rats, i.e. a widely-used model of complex-partial seizures (limbic epilepsy). In the present experiments, different categories of ligands for the NMDA receptor-associated glycine modulatory site were evaluated in the kindling model in rats. For this purpose, the ‘silent’ glycine antagonist 7-chlorokynurenic acid (7-CKA), the low efficacy glycine partial agonist (+)-HA-966( R(+)-3-amino-1-hydroxypyrrolid-2-one), and the high efficacy glycine partial agonist d-cycloserine (D-CS) were used. In view of the poor brain penetration of some of these compounds after systemic administration, all drugs were injected bilaterally into the lateral ventricles of fully kindled rat. Anticonvulsant activity was evaluated by determination of the threshold for induction of focal afterdischarges in the amygdala (ADT) and by monitoring seizure parameters (seizure severity, seizure duration, afterdischarge duration) at ADT current. In addition to anticonvulsant activity, the behavioural adverse effects of test drugs were determined. All three drugs increased the focal seizure threshold, although at different potencies. In terms of injected dosages and percentage ADT increase, the most potent compound was 7-CKA, followed by (+)-HA-966 and D-CS. None of the drugs induced behavioural adverse effects or motor impairment (measured in the rotarod test) at anticonvulsant doses. However, D-CS produced proconvulsant effects at higher doses. The data demonstrate that pharmacological manipulation of the glycine modulatory site of the NMDA receptor is an effective means of increasing seizure threshold in amygdala-kindled rats. In this respect, glycine antagonists and partial agonists are clearly superior to competitive or uncompetitive NMDA receptor antagonists. Systemically active glycine antagonists or partial agonists may thus provide a novel strategy for treatment of limbic seizures.

Synergistic effect between intraneoplastic methotrexate and radiation on experimental intracerebral rat gliosarcoma.

Methotrexate (MTX) alone has a limited effect against malignant brain tumors, but we previously demonstrated a beneficial synergism between MTX and radiation therapy (XRT) against RT-9 gliosarcoma. Because the beneficial effects of that study were limited by systemic toxicity and poor brain penetration of MTX, we have continued our studies using direct intracerebral MTX therapy. Male CD-Fisher rats with intracerebrally implanted RT-9 gliosarcoma and indwelling brain tumor catheters were treated with intracerebral injections of MTX, whole-brain XRT, or a combination of both. MTX was given either as one of two "high-dose" treatments, on the basis of whole-body doses, or two "low-doses," on the basis of average brain weight. MTX alone at lower doses and XRT alone each prolonged survival moderately. High-dose MTX was highly toxic, but low-dose MTX was well tolerated. Combined MTX and XRT caused a significant prolongation of survival in all animals that survived treatment long enough to die from tumor growth.

Measurement of central nervous system activity of systemically administered CCK B receptor antagonists by ex vivo binding

In the present study we have described an ex vivo binding assay in mice to measure the central nervous system (CNS) activity of systemically administered CCK B receptor antagonists. This assay incorporated a transcardiac perfusion step to remove the residual blood from the brain, which otherwise may result in an overestimation of CNS activity. The benzodiazepine CCK B receptor antagonist L-365,260 had marked CNS activity in this assay following i.v. (ED 50 12.0 mg/kg) and p.o. (ED 50 20.0 mg/kg) administration, whereas the dipeptoid CCK B receptor antagonist, CI988 exhibited relatively weak CNS activity following i.v. injection (ED 50 > 30.0 mg/kg). In contrast, following i.c.v. administration, CI988 potently inhibited ex vivo binding of [ 125I]Bolton Hunter-CCK-8S to mouse brain. The recently described acidic tetrazole CCK B receptor antagonist, L-368,935 had potent CNS activity with an ED 50 of 5.6 mg/kg i.v. and an ED 50 of 1.9 μg/kg i.c.v. These studies suggest that the weak CNS activity of CI988 following systemic injection may, in part, be due to poor brain penetration and that the ex vivo binding assay is a useful way of assessing the brain penetration of CCK B receptor antagonists.

Competitive as well as uncompetitive N-methyl-D-aspartate receptor antagonists affect cortical neuronal morphology and cerebral glucose metabolism

The studies examined the effects of three antagonists (CPP, CGS 19755, and CGP 37849) that act competitively at the glutamate recognition site of the NMDA receptor complex on cortical neuronal morphology and cerebral limbic glucose metabolism. Responses were compared to the effects of dizocilpine, an uncompetitive NMDA receptor ion channel antagonist as a positive control. CGS 19755 and CGP 37849 (100 mg kg-1 i.p.) caused vacuolation in cortical pyramidal neurons in the posterior cingulate cortex four hours after dosing and this dose of CGP 37849 caused a pattern of limbic glucose metabolism activation similar to that seen after dizocilpine. CPP was without effect at 100 mg/kg i.p. probably due to poor brain penetration. The data indicates that the functional consequences (structural and metabolic) of NMDA receptor blockade with NMDA antagonists acting competitively at the glutamate recognition site and uncompetitively in the receptor ion channel are ultimately the same. Comparisons of the potential therapeutic window for CGS 19755 and CGP 37849 with dizocilpine (neuroprotection versus vacuolation) suggests that the window for the competitive antagonists is greater. This indicates that the potential therapeutic window for the different classes of NMDA antagonists may vary with the site in the receptor complex at which they interact.

Brain Targeting of anti-HIV Nucleosides: Ether Prodrugs of 3′-Azido-2′,3′-Dideoxyuridine (AZdU) and 3′-Azido-3′-Deoxythymidine (AZT)

In an effort to increase the brain delivery of anti-HIV nucleosides, 5-0-benzyl and glucose derivatives of 3′-azido-2′,3′-dideoxyuridine (AZdU or CS-87) and 3′-azido-3′-deoxythymidine (AZT) were synthesized. In vitro stability and pharmacokinetic studies in mice were conducted with benzyl AZdU (BzlAZdU), benzyl AZT (BzlAZT), and glucose AZdU (GAZdU) prodrugs. In vitro studies indicated that the prodrugs were stable in phosphate buffer (pH 7.4), human serum and mouse serum. In mouse brain homogenate, the degradation half-lives for BzlAZdU, BzlAZT, and GAZdU were 1.66, 2.06, and 0.98 h, respectively, and in liver homogenate the degradation half-lives were 0.49, 0.29, and 1.97h, respectively. Following intravenous administration of BzlAZdU, BzlAZT, or GAZdU to mice, prodrug and parent drug concentrations were measured in serum and brain by HPLC, and pharmacokinetic parameters determined. The brain:serum area under the concentration time-curve (AUC) ratio, a parameter indicative of prodrug uptake into brain, was 0.55 for BzlAZdU and 0.56 for BzlAZT, compared to 0.05–0.08 when the parent drugs AZdU and AZT were administered intravenously. GAZdU had poor brain penetration, achieving brain concentrations of only 5% of the serum concentrations. Parent drug concentrations in brain were, for the most part, not detected after administration of any of the prodrugs. Consistent with in vitro data, it is apparent that the prodrugs were converted to metabolites other than the parent drug species.

Inhibition of catechol- O-methyltransferase (COMT) as well as tyrosine and tryptophan hydroxylase by the orally active iron chelator, 1,2-dimethyl-3-hydroxypyridin-4-one (L1, CP20), in rat brain in vivo

The orally active iron chelator, 1,2-dimethyl-3-hydroxypyridin-4-one (L1, CP20) proposed for reduction of iron overload in hemoglobinopathic patients, was studied in rats with respect to its ability to interfere with dopamine (DA) and serotonin (5-HT) metabolism. At 100 mg/kg i.p., it reduced the levels of DA, 5-HT, 5-hydroxyindoleacetic acid and particularly homovanillic acid in the rat striatum for several hours. These effects were shown to result from concomitant inhibition of catechol- O-methyltransferase (COMT; EC 2.1.1.6), tyrosine [tyrosine, tetrahydropteridine:oxygen oxidoreductase (3-hydroxylating) (EC 1.14.16.2)] and tryptophan hydroxylase [tryptophan, tetrahydropteridine:oxygen oxidoreductase (5-hydroxylating) (EC 1.14.16.4)], with similar time-courses. COMT was inhibited with a threshold dose of about 1 mg/kg i.p. and an ed 50 of about 10 mg/kg i.p. as determined by the conversion of exogenous l-dihydroxyphenylalanine ( l-DOPA) to its O-methylated derivative. Tyrosine and tryptophan hydroxylase activities as measured by the accumulation of DOPA and 5-hydroxytryptophan, respectively, after central decarboxylase inhibition, were inhibited in striatum and cortex, with threshold doses of 3–10 mg/kg and ed 50s of about 20–30 mg/kg i.p. or p.o. While COMT inhibition by L1 is probably related to the structural similarity of the latter drug with the normal enzyme substrates, tyrosine and tryptophan hydroxylase inhibition is more likely due to coordination to iron bound to these enzymes. Desferrioxamine at 100 mg/kg i.p. did not show comparable effects. It is not known whether this relates to poor brain and/or cell penetration, or whether multidentate chelators are less suitable as inhibitors of aromatic amino acid hydroxylases

The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor

The selective non-competitive NMDA receptor antagonist, MK-801, potently blocked convulsions induced in the mouse by N-methyl-DL-aspartic acid (NMDLA) with an i.v. ED 50 dose of 0.2 mg/kg. Similar doses of MK-801 were also effective in blocking seizures induced by pentylenetetrazol (PTZ), electroshock and by sound in audiogenic seizure-prone animals. Other less selective non-competitive NMDA receptor antagonists including phencyclidine (PCP), thienylcyclohexylpiperidine (TCP), (+)-N-allylnormetazocine ((+)-NANM, (+)-SKF 10,047) and ketamine also blocked NMDLA-induced seizures with a rank order of potency of MK-801 > PCP > TCP = (+)-NANM > ketamine. The competitive NMDA receptor antagonist, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) blocked NMDLA-induced seizures with an ED 50 of 4.5 mg/kg, 22- and 560-fold more potently than the competitive antagonists, 2-DL-amino-7-phosphonoheptanoic acid (2-APH) and 2-DL-amino-5-phosphonovaleric acid (2-APV), respectively. MK-801 was the most potent of the non-competitive antagonists to induce a motor syndrome including head weaving, body rolling, increased locomotion and ataxia, characteristic of the behavioural response to PCP in the mouse. The syndrome was also present following injection of the competitive NMDA receptor antagonists, although they were generally less potent (probably a reflection of poor brain penetration) and less efficacious than the non-competitive antagonists. For all compounds except CPP, the anticonvulsant ED 50 dose was close to the minimun effective dose to induce motor stimulation: CPP was 5- to 10-fold more potent as an anticonvulsant. In drug discrimination studies, MK-801 induced a highly discriminable interoceptive stimulus to which other non-competitive NMDA receptor antagonists dose dependently generalised. CPP partially generalised to the MK-801 stimulus. Overall, the results provide strong support for the hypothesis that antagonism of NMDA receptors is a major event in the genesis of many of the behavioural responses to MK-801 and phencyclidine.

The Additional Properties of Beta Adrenoceptor Blocking Drugs

Beta adrenoceptor blocking drugs are all competitive inhibitors of the beta receptor although they may or may not possess, beta 1-(cardio)selectivity, intrinsic sympathomimetic activity (ISA) or partial agonist activity, alpha-blocking properties, while membrane stabilizing activity is now thought not to be important. Drugs with ISA give less of a reduction in resting and maximal exercising heart rate and consequently in cardiac output, than those without ISA. The possession of alpha-blocking activity also leads to less fall in cardiac output. Overall evidence suggests that peripheral resistance and peripheral blood flow is less reduced by ISA drugs. Post-beta blockade hypersensitivity which may be important in patients with ischemic heart disease if beta blocking drugs are suddenly stopped, is absent after beta-blocking drugs with ISA as they result in down regulation of beta receptors. Beta 1-selective drugs may result in less of a rise in blood pressure in response to isometric exercise, insulin hypoglycemia or smoking. There do not appear to be important differences in the effect on coronary flow. While presently available drugs can produce asthma in susceptible subjects there seems little doubt that beta 1 selective agents have less effect than other beta-blocking drugs, and give less inhibition of sympathomimetic bronchodilators. Nonselective, non ISA, beta-blocking drugs elevate triglycerides, cardioselective drugs possibly less so. Those with ISA may elevate HDL unlike those beta-blocking agents without this property. Beta adrenergic blocking drugs without ISA do not lower resting plasma noradrenaline, evidence suggests an increase; whereas those agents with marked ISA, suggests an increase; whereas those agents with marked ISA, e.g., pindolol, reduce it. Renin levels are lowered, but less so with ISA possessing agents. Some agents, e.g. atenolol, nadolol, sotalol, are hydrophilic, show poor brain penetration, are long-acting, are not liver metabolized, but are excreted by the kidneys unchanged. Others are lipophilic, e.g., metoprolol, propranolol, penetrate the brain, and are liver metabolized. Pindolol is metabolized about 50% by each route. Similarities between beta blocking drugs are dominant but differences are often clinically relevant.