Carl Kaiser

Studies on renal dopamine receptors with a new agonist

SK & F 38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine) is a new dopamine receptor agonist which selectively increased renal blood flow when administered i.v. to dogs at cumulative doses of 3.3-1333 microgram/kg. Consistent changes in arterial blood pressure heart rate and cardiac output were not observed. The renal response, which was mediated locally in the kidney, was not antagonized by adequate blocking doses of atropine, propranolol, metiamide and/or mepyramine nor by reserpinization or treatment with indomethacin. It was inhibited, however, by the selective peripheral dopamine receptor antagonist, bulbocapnine. Perhaps as a result of its action on renal blood flow, SK & F 38393 produced a diuresis in normally hydrated rats which was characterized by an increased excretion of sodium, potassium and chloride and a increased urinary pH. Compounds of this type may be useful in better defining dopaminergic receptors and in the treatment of disease states where renal ischemia is present.

[125I]SCH 23982: the ligand of choice for identifying the D-1 dopamine receptor

[125I]SCH 23982, [125I]8-iodo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol, binds reversibly and with high affinity (Kd = 0.7 +/- 0.05 nM) to specific binding sites (maximum binding = 108 +/- 3.5 fmol/mg) in the caudate nucleus of the rat brain. The caudate binding site displays pharmacological properties similar to the D-1 receptor; furthermore, the site has a low affinity for drugs favoring the D-2 receptor. GTP diminishes the affinity of dopamine, a D-1 agonist, but not SCH 23390, a D-1 antagonist, for the caudate binding site. The iodinated ligand discriminates between the D-1 and the D-2 dopamine receptors: the neurointermediate lobe of the rat pituitary gland, a tissue rich in D-2 dopamine receptors, possesses less than 4% of the specific binding sites in the caudate. Because [125I]SCH 23982 exists at a higher specific activity than [3H]SCH 23390, a ligand used previously to identify the D-1 receptor, and because the results obtained with the iodinated ligand are otherwise similar to those obtained with the [3H]SCH 23390, [125I]SCH 23982 is the ligand of choice for identifying the D-1 receptor.

Studies on the mechanism of phenylethan-olamine-N-methyl-transferase inhibition by a dichloro-substituted benzimidazole

Abstract 2-Amino-5-6,-dichlorobenzimidazole (DCB) is the most potent inhibitor in vitro of phenylethanolamine- N- methyl-transferase (PNMT) known; in our laboratory its I 50 for inhibiting a partially purified rabbit adrenal enzyme preparation with norepine-phrine and S -adenosylmethionine as co-substrates was 4 × 10 −7 M. DCB was not a substrate for PNMT at concentrations encompassing its inhibitory range (10 −4 −10 −8 M) and its antagonistic effect upon the enzyme after 30 min of preincubation was reversible. Kinetically, DCB was a noncompetitive inhibitor of norepinephrine and antagonized S -adenosylmethionine uncompetitively. Thus, the inhibition produced by this compound was not surmountable by either substrate. In kinetic studies at 1 × 10 −4 M, epinephrine behaved as did DCB, which demonstrates a similarity in the mode of inhibitory action of the two compounds.

Structure—Activity Relationships of Dopamine Receptor Agonists

Dopamine (DA*), which is chemically defined as β-(3,4-dihydroxyphenyl) ethylamine, 3-hydroxytyramine, or 5-(2-aminoethyl)-1,2-benzenediol, was first synthesized in 1910 (Mannich and Jacobsohn, 1910). At that time it was classified as a sympathomimetic amine because only its epinephrinelike actions were known (Barger and Dale, 1910). Although its formation from L-Tyr via L-DOPA was recognized (Blaschko, 1939; Holtz, 1939), DA was not identified in the mammalian organism and shown to have pharmacological actions differing from those of epinephrine until 1942 (Holtz et al., 1942). It was first shown to be present in mammalian tissue by Goodall (1950a,b, 1951). Blaschko (1957) first suggested an independent physiological role for DA in the periphery. More recently, DA has been identified as a neurotransmitter in the CNS (Carlsson et al., 1958; Carlsson, 1959; Goodall and Alton, 1968; Hornykiewicz, 1971).

Chapter 1. Antipsychotic and Anti-anxiety Agents

Publisher Summary This chapter presents results of studies that analyze antipsychotic and antianxiety agents. The use of long-acting fluphenazine in the management of schizophrenia and its comparison with conventional therapy was reviewed. Studies of other 6-6-6 tricyclics included several new phenothiaaine derivatives. A diazabicyclononane analog of chlorpromazine (CPZ), one of a series, presented a typical neuroleptic profile. The sulfone derived from thioridazine, that is, inofal caused improvement in two-thirds of a group of chronic schizophrenic females. A valeroylphenothiazine, MB however, a clearcut correlation with antipsychotic efficacy was not observed. Metabolic studies of piperazine-bearing phenothiazine antipsychotics in rats and dogs demonstrated the formation of ethylenediamine derivatives from prochlorperazine and trifluoperazine. The distribution and metabolism of azaperone, a neuroleptic which induces rapid sedation, was studied in rats and pigs. Clorazepate dipotassium, marketed in the United States in 1972, was also studied in the clinic and in animals.

Chapter 1. Antidepressants

Publisher Summary This chapter discusses a great many clinical, pharmacological, pharmacokinetic, metabolic, and, perhaps most importantly, mechanistic studies of antidepressants. The side effects of the existing agents, particularly cardiotoxicity, anticholinergic actions, neuroendocrine dysfunction, and akinesia, have been the subject of this comprehensive review. Recent advances in predictive test procedures and in understanding of the mechanism of action provide a basis for optimism that novel efficacious antidepressants may be forthcoming. Several series of tricyclic compounds with antidepressant (TCA) activity bear a piperazinyl side chain. The thienobenzoxazepine was 0.4 times as potent as imipramine as an antagonist of tetrabenazine-induced depression in mice; it also caused neuroleptic effects, as it afforded protection against amphetamine-induced lethality in grouped mice. As new TCAs, aminoacyl and aminoalkyl derivatives of indolobenzodiazepines potently inhibit tetrabenazine-induced ptosis in mice, whereas the octahydrodibenzazepinonaphthyridine isomers, rigid congeners of imipramine, have TCA-like activity in blocking norepinephrine (NE) and dopamine (DA) uptake and in binding studies with rat brain homogenate. Chronic administration of TCAs, MAOIs, Iprindole, and Bupropion, but not of Mianserin or other psychotropic drugs decreases β-adrenergic receptor binding in rat cortex. Mianserin and Zimelidine reduce the NE-stimulated cAMP response, but not the density of B-adrenergic receptors in rat cortex following chronic administration.

Effect of 2-(p-chlorophenyl)cyclopropylamine on 5-hydroxyindole concentration and monoamine oxidase activity in rat brain

p-Chloroamphetamine (PCA) causes a rapid and long-lasting depletion of serotonin in rat brain [l]. PCA is thought to affect serotonin neurons acutely by (a) inhibition of tryptophan hydroxylation, (b) release of vesicular bound serotonin, (c) inhibition of serotonin reuptake from the synaptic cleft, and (d) inhibition of serotonin oxidation by monoamine oxidase, and to produce neurotoxic degeneration of some serotonin neurons resulting in a chronic decrease in tryptophan hydroxylase activity, serotonin and S-hydroxyindoleacetic acid (S-HIAA) concentration, and serotonin uptake capacity (variables associated specifically with serotonin neurons). Among the analogs of PCA that have been studied [I], N-cyclopropyl-PCA is characterized by being a potent irreversible inhibitor of monoamine oxidase [2]. Its relatively greater inhibition of monoamine oxidase than that by PCA results in serotonin concentration not being decreased initially (during the first 24 hr), whereas at 1 week, when the monoamine oxidase-inhibiting effects have diminished, serotonin concentration is decreased [2]. 5HIAA concentration decreases rapidly and remains decreased at 1 week after N-cyclopropyl-PCA injection [2]. Thus, N-cyclopropyl-PCA (a) inhibits monoamine oxidase and (b) has PCA-like serotonin-depleting activity. These two actions have been dissociated first by giving harmaline, which protects against the irreversible inactivation of type A monoamine oxidase by N-cyclopropylPCA and exposes its ability to deplete serotonin earlier (31, and second by giving fluoxetine. which inhibits Ncyclopropyl-PCA uptake into serotonin neurons and thus prevents its depletion of serotonin but permits monoamine oxidase inhibition to occur [4]. We are describing here studies on a PCA analog similar in structure to N-cyclopropyl-PCA but with the cyclopropyl group interposed between the p-chlorophenyl group and the amino group. The structure of this compound. 2-(pchlorophenyl) cyclopropylamine (PCCA), is shown in Fig. 1 compared to PCA and N-cvclopropvl-PCA. In these experiments, 13&20dg male Wistar rats from Harlan Industries, Cumberland, IN, were used. The rats were housed in hanging wire cages in a light-controlled room (12 hr light/l2 hr dark) and had free access to food and water. PCCA hydrochloride was synthesized at the Smith Kline & French Laboratories. Chromatographic and spectral data indicated that it consists of 77.6% tram and 22.4% cls isomers. Harmaline hydrochloride was purchased from the Sigma Chemical Co., St. Louis, MO. PCCA was injected at a dose of 0.05 mmole/kg, the same as that used previously for N-cyclopropyl-PCA [2]. Both drugs were injected i.p. in aqueous solutions. Rats were decapitated after treatment, and brains were rapidly excised. split longitudinally along with the midline. and frozen on dry ice. Tissue samples were stored at 15” prior to analysis. Serotonin and 5-hydroxyindoleacetic acid concentrations were determined spectrofluorometrically after extraction and reaction with o-phthalaldehyde by the method of Miller et al. [5]. Monoamine oxidase activity was assayed with 100 pM [14C]serotonin or 80 pM [“C]phenylethylamine (from New England Nuclear. Boston, MA) as substrate [6]. The effects of PCCA on 5-hydroxyindole concentrations in rat brain at various times are shown in Table 1. Within p-Chloroamphetamine (PCA)

Chapter 5. Antidepressants

Publisher Summary This chapter discusses the objectives to develop new anti-depressant drugs with fewer side effects and a rapid onset of action. Tricyclic compounds with antidepressant activity (TCAs), their therapeutic utility, biology, metabolism, and side effects also combined TCA-antipsychotic therapy was investigated. The influence of the seven-membered ring conformation of “6-7-6” TCAs and imine analogs of TCAs were studied of which the cyclopropa(c)cycloheptene derivatives were the most potent. Alprazolam, a benzodiazepine derivative with combined anti-anxiety–anti-depressant actions, was the most effective. Presynaptic α-blockade was noted only in molecules with an overall bent shape. “Second generation” antidepressants were discussed in the chapter. 2-C 6 H 5 CH 2 C 6 H 4 O(CH 2 ) 4 NHCH 3 (MCI-2016) was one of the most potent members (0.78x amihptyline) of aminoalkoxyaryl compounds in a test for the prevention of reserpine-induced hypothermia in mice. Antidepressant actions were also produced by many bicyclic compounds. Foremost among these were 1,4-benzodiazepines and related structures that combine anti-anxiety and anti-depressant actions. A number of quinolines and related structures have antidepressant properties. The piperazinylquinoline DU 24565, a quipazine analog and 5-HT uptake inhibitor, is being studied as a potential antidepressant. Several ben-zodioxanylimidazoline apparently owe their antidepressant activity to blockade of central α 2 -adrenergic receptors. Anti-depressant effects have been associated with thyrotropin releasing hormone (TRH), pyroGlu-His-ProNH 2 , a peptide that potentiates the effects of imipramine on brain 5-HT systems. Monoamine oxidase inhibitors (MAOIs) investigations indicate greater anti-depressant efficacy for (+)-tranylcypromine, the more potent MAOI, than for the (-) isomer, a more effective uptake inhibitor. Central nervous system (CNS) stimulant effects of caffeine was recently correlated with their ability to bind to central adenosine (A 1 and A 2 ) receptors, thus preventing the depressant action of endogenous adenosine on nerve firing. ECS therapy, for which memory impairment is a major side effect, may find increased application in the future because new technologies are enhancing its precision, efficacy, and safety.

Chapter 2. Antidepressives and Stimulants

Publisher Summary This chapter discusses the biochemistry and pharmacology of antidepressives and stimulants. The synthesis and pharmacological evaluation of numerous potential antidepressives are presented. An amitriptyline derivative, exhibited a pharmacological profile similar to that of the parent. Antidepressive and antianxiety properties were also noted for a monomethyl analog. A dibenzthiepin, dothiepin, was superior to amitriptyline in a double blind comparison for the treatment of depression. Amoxapine, a dibenzoxazepine, although devoid of anticholinergic properties, produced imipramine-like activity in animals. Structure versus anti-depressive activity relationships were reported for a series of phenothiazines and related compounds bearing a carbocyclic basic side chain. The phenothiazines with antidepressive actions included the l-chloro-analog of chlorpromazine, which produced imipramine-like actions in mice and rats, and the azaphenothiazine-10-thiolcarboxylate, which induced antidepressive-like symptoms in mice. The antidepressive effects of phenothiazine derivatives with 1- or α-substituents may be associated with the steric influence of these groups in interfering with attainment of a nearly flat conformation by the tricyclic system.