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The pharmacological profile of a new bicyclic substance, Lu 10-171 (1-(3-(dimethylamino)propyl)-1-(p-fluorophenyl)-5-phthalancarbonitril), is described and compared with that of existing tricyclic thymoleptics. In mice and rats the compound exhibited marked 5-HT potentiating properties both in vivo and in vitro, being 5-10 times as active as chlorimipramine. The tests included 5-HT-, 5-HTP- and tryptophan-potentiation. In monoamine oxidase inhibitor treated dogs and rabbits the compound caused a marked hyperthermia. In rabbits this effect was completely blocked by pretreatment with the tryptophan hydroxylase inhibitor, p-chlorophenylalanine. Hyperthermia induced by the central catecholamine displacing substance H 77/77 in rats was not affected by Lu 10-171, whereas the substance abolished the temperature rise induced by H 75/12. Reserpine- and tetrabenazine-induced ptosis and tetrabenazine-induced immobility in mice were antagonized by relatively low doses of existing tricyclic thymoleptics, whereas Lu 10-171 was very weak in this respect. Very weak in vitro anticholinergic and antihistaminergic properties were also registered for Lu 10-171. It is concluded that Lu 10-171 is a very potent and highly specific potentiator of 5-HT both in vivo and in vitro probably due to inhibition of 5-HT uptake. Thus this compound might be a useful agent in studying the role of 5-HT neurone systems in the control of mood. The substance does not possess the NA potentiating and anticholinergic and antihistaminergic properties characteristic of the tricyclic antidepressants.
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PMID:Pharmacology of a new phthalane (Lu 10-171), with specific 5-HT uptake inhibiting properties. 1 88

Effects of methyl o-(4-hydroxy-3-methoxycinnamoyl) reserpate (CD-3400) on the central nervous system in mice, rats and cats were investigated, and a comparison was made with such effects of reserpine and rescinamine. Inhibitory effects of CD-3400 on spontaneous motor activity and conditioned avoidance response were weaker and shorter than those of reserpine and rescinnamine. In the experiments of the inhibitory effects of the central actions such as ptosis, hypothermia, decrease in motor ability, potentiation of hexobarbital and taming, reserpine was found to be the most potent followed by rescinnamine and CD-3400, respectively. High doses of CD-3400 exhibited inhibitory effects on methamphetamine-induced hyperactivity in mice and this action was weaker than those of reserpine and rescinnamine. CD-3400, 80-160 mg/kg p.o., showed no significant effects on morphine-induced analgesia, while a slight inhibition was observed on the Straub-tail reaction using morphine. Reserpine, 0.5 mg/kg i.v., resulted in a drowsy pattern in the spontaneous EEG activity and the EEG arousal response was depressed, while with CD-3400, 5 mg/kg i.v., there was no drowsy pattern. CD-3400 as well as rescinnamine and reserpine remarkably depleted 5-HT levels in brain, heart and plasma and the potency of CD-3400, particularly in the brain, was weaker than the potency of reserpine and rescinnamine. These results indicate that CD-3400 is an antihypertensive agent with a low toxicity and a weak central action.
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PMID:[Inhibitory effects of methyl o-(4-hydroxy-3-methoxycinnamoyl) reserpate (CD-3400) on the central nervous system (author's transl)]. 2 46

The purpose of this study was to determine the nature of the argyrophilic cells in the ectocervix and to analyze the different morphologic varieties of argyrophil cell-containing ectocervical epithelia, notably to reappraise the degree of analogy with transitional epithelium. A systematic study of 39 ectocervices was carried out using histochemical and immunohistochemical techniques. Immunodetection of cytokeratins was used to specify the differentiation of the ectocervical linings. Argyrophilic cells were detected in 43% of our specimens. They have been found in several varieties of ectocervical lining: normal-appearing or hyperkeratotic squamous epithelium, "transitional-like" epithelium extending onto the portio, and immature squamous metaplasia from the transformation zone. The term "transitional-like" refers to a stratified nonsquamous epithelium that differs from true urothelium by the absence of superficial differentiation leading to the layer of "umbrella" cells. Two main types of argyrophilic cells have been delineated: serotonin cells and Merkel-type cells. The nature of the argyrophilic cells was dependent on the type of epithelium: Serotonin cells were essentially associated with "transitional-like" epithelium and Merkel-type cells with squamous epithelium. The latter cells were particularly frequent in hyperkeratotic squamous epithelium from uterine prolapse, reinforcing the homology with epidermis.
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PMID:Argyrophilic cells and ectocervical epithelium. 170 23

2-(3,4-Dichlorobenzyl)-2-dimethylamino-1-propanol, hydrochloride (JO 1017) is a novel antidepressant drug. Its biochemical and pharmacological properties were investigated in mice, rats, dogs, rabbits and guinea pigs. In vitro, it selectively inhibited serotonin uptake and had a high affinity for the 3H-paroxetine and 3H-imipramine binding sites. Biochemical studies demonstrated the lack of MAO-A and MAO-B inhibition and the absence of marked affinity for muscarinic, histaminic or other conventional brain receptors. Chronic treatment with JO 1017 induced a decrease in the Bmax values for imipramine sites but did not modify the Bmax for beta-adrenergic and 5-HT2 receptors. The neuropsychopharmacological profile of JO 1017 is characterized by a decrease of the immobility times in behavioural despair tests with mice, a decrease of the escape failures in the rat learned helplessness test, a strong potentiation of L-5-HT P-induced head-twitches in mice and an antagonism of reserpine-induced ptosis in rabbits. It weakly antagonized oxotremorine-induced hypothermia and did not influence the hypothermia induced by apomorphine. In contrast to most other antidepressants, a high dose of JO 1017 induced hypermotility in mice placed in an activity meter without producing stereotyped behaviour and group toxicity. Unlike tricyclic antidepressants, JO 1017 was devoid of severe cardiotoxicity in guinea pigs and had no central anticholinergic nor antihistaminic properties. These results suggest that JO 1017 is a selective serotonin uptake inhibitor with a high safety margin. JO 1017 may have a potential clinical utility both in the treatment of depression and for indications where serotonin transmission is involved, e.g., anxiety, panic attack, obsessive compulsive disorder, obesity and alcohol consumption.
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PMID:Biochemical and pharmacological evaluation of the novel antidepressant and serotonin uptake inhibitor 2-(3,4-Dichlorobenzyl)-2-dimethylamino-1-propanol hydrochloride. 216 3

Behavioural effects on dopaminergic transmission of a phenylindane derivative, Lu 19-005 [(+/-)-trans-3-(3,4-dichlorophenyl)-N-methyl-l-indanamine, HCI], with potent inhibitory effect on dopamine (DA), noradrenaline (NA) and serotonin (5-HT) uptake in rats and the effect on DA, NA and 5-HT activity in mice have been studied and compared with those of other known DA, NA and 5-HT uptake inhibitors with different selectivity ratios. Lu 19-005 induced stereotyped behaviour after parenteral and oral administration with a duration of action of more than 24 h. The stereotyped licking and biting induced by Lu 19-005 was antagonized by reserpine and cis(Z)-flupentixol, but not affected by prazosin, p-chlorophenylalanine and alpha-methyl-p-tyrosine pretreatments. Metergoline slightly facilitated the onset of stereotypy. Lower doses of Lu 19-005 induced ipsilateral circling in unilaterally 6-hydroxy-DA-lesioned rats. Finally, Lu 19-005 antagonized the catalepsy induced by perphenazine. In mice, Lu 19-005 potentiated the apomorphine-induced gnawing, reversed tetrabenazine-induced ptosis and potentiated the behavioural effects of 5-HTP within a similar dose range. The effects of Lu 19-005 were compared with those of other reference compounds. Nomifensine had qualitatively similar effects in rats although of much shorter duration. In mice, nomifensine selectively reversed tetrabenazine-induced ptosis. Weaker effects in all test models were found with bupropion, LR 5182 and GBR 13.069, compounds with inhibitory effect on DA and NA uptake. The DA-, NA- and 5-HT-uptake inhibitor diclofensine, however, had no effect in rats except in the 6-hydroxy-DA-circling test and had low potency in mice. The specific 5-HT- and NA-uptake inhibitors citalopram and talsupram, respectively, were ineffective in all rat models.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacology in vivo of the phenylindan derivative, Lu 19-005, a new potent inhibitor of dopamine, noradrenaline and 5-hydroxytryptamine uptake in rat brain. 240 54

A potential antidepressant activity of B-193 was studied in mice and rats. In in vitro studies B-193 did not affect the uptake of NA and 5-HT. In in vivo models the tested compound did not influence the reserpine-induced hypothermia, hypoactivity and ptosis, the stimulating action of L-DOPA, the apomorphine-induced hypothermia. On the other hand, it produced a positive effect in the despair test. When given repeatedly, it evoked adaptive changes in brain neurotransmitter receptors, i.e. it decreased the density of beta-adrenoceptors and increased the number of alpha 1 ones; those changes were accompanied with functional alternations in the reactivity of those receptors: an attenuated behavioral reaction to salbutamol and enhanced aggressiveness induced by a high dose of clonidine. Furthermore, B-193 administered repeatedly enhanced hyperlocomotion induced by amphetamine but did not influence the stereotypy induced by apomorphine. These results indicate that B-193 possesses properties characteristic for atypical antidepressants.
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PMID:Antidepressant profile of 9-methyl-2[-3-(4-phenyl-1-piperazinylpropyl)]-1,2,3,4-tetrahydro-beta- carbolin-1-one (B-193). 263 91

A series of pyrrolo[2,1-a]isoquinolines, and related compounds, were examined for antidepressant-like activity, by virtue of their antagonism of tetrabenazine-induced ptosis and sedation, and inhibition of biogenic amine uptake. Thus, we have identified some of the most potent antagonists of TBZ-induced ptosis and some of the most potent inhibitors of the uptake of dopamine, norepinephrine, and serotonin (in rat brain synaptosomes) ever reported. Compounds of particular note, in this regard, are 52b, 29b, 22b, and 48b, respectively. Biological activity was chiefly manifested by the trans isomeric class. Also, through resolution of four compounds, 7b, 24b, 37b, and 48b, biological activity was found to be associated with the (+) enantiomer subgroup (salts measured at 589 nm in MeOH), corresponding to the 6S, 10bR absolute configuration for 7b, 37b, and 48b, and the 6R,10bR configuration for 24b. An X-ray determination on (+)-24b X HBr established its absolute configuration; configurations for the other compounds were verified by enantiospecific synthesis starting with (+)-(R)-2-phenylpyrrolidine. Regarding the pendant phenyl ring, diverse substitution patterns were investigated. Those substitutions that were particularly unfavorable were 3',4',5'-trimethoxy (20b), 2',3',4',5',6'-pentafluoro (34b), 2'-trifluoromethyl (38b), 3',5'-bis(trifluoromethyl) (42b), 4'-n-butyl (44b), 2'-cyano (47b), 4'-methylsulfonyl (50b), and 2'-carboxy (58b). Exceedingly potent compounds, in one way or another, were 10b-12b, 22b, 23b, 25b, 28b, 29b, 33b, 45b, 48b, 51b-53b. The pattern of aromatic substitution had a strong impact on selectivity in the uptake tests (NE vs. DA vs. 5-HT). Activity was significantly diminished by methyl substitution of 7b at the 5 (65, 66), 6 (61b), or 10b (60b) position, by changing the phenyl group of 7b to cyclohexyl (67b), benzyl (68b), or H (72), by moving the phenyl group of 7b to the 5 (69) or 10b (70) position, by expansion of ring B to an azepine (78b), and by modification of ring C to an azetidine (77b), piperidine (75b), or azepine (74b). The interaction of selected analogues with various CNS receptors is reported. Little affinity was shown for the muscarinic cholinergic receptor, suggesting a lack of anticholinergic side effects. Interestingly, 24b and 33b displayed a high affinity for the serotonin-2 receptor, analogous to mianserin and clomipramine. After the body of data was reviewed, derivatives 24b and 48b were chosen for advanced development.
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PMID:Pyrroloisoquinoline antidepressants. 2. In-depth exploration of structure-activity relationships. 303 36

24 h pretreatment with molindone enhanced the behavioural effects of L-dopa and 5-HTP, precursors of biogenic amines (catecholamines and 5-HT respectively) preferentially deaminated by MAO-A, confirming that a metabolite of molindone inhibits MAO-A. 24 h pretreatment with molindone enhanced the behavioural effects of tryptamine and antagonized reserpine-induced ptosis, and in molindone-pretreated rats L-tryptophan induced behavioural effects, probably because of the MAO-A inhibitory activity exerted by a metabolite of molindone. Since 24 h pretreatment with molindone, unlike 30 min pretreatment with clomipramine, failed to antagonize fenfluramine and p-chloramphetamine-induced behavioural syndromes, it suggests that molindone and/or its metabolites most probably do not exert 5-HT neuronal uptake blocking activity and the potentiation of 5-HTP-induced behavioural syndrome is due to a metabolite's MAO-A inhibitory activity. As 2 h pretreatment with molindone induced catalepsy and antagonized apomorphine-induced climbing behaviour in mice and stereotypy in rats, while 24 h pretreatment failed to induce catalepsy and to antagonize apomorphine-induced behaviour, it appears that, at 24 h, the tissue levels of molindone are inadequate to block postsynaptic striatal and mesolimbic DA receptors and that, though a metabolite of molindone is biologically active so far as inhibition of MAO-A is concerned, the metabolites are devoid of neuroleptic activity. Further, since 2 h pretreatment with molindone failed to enhance the behavioural effects of L-dopa, it suggests that at 2 h the degree of MAO-A inhibition induced by molindone and/or the metabolite is not sufficient to counteract the neuroleptic activity of the parent compound.
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PMID:Psychopharmacological investigation of the monoamine oxidase inhibitory activity of molindone, a dihydroindolone neuroleptic. 614 85

A series of substituted 4-aryltetrahydrothieno[2,3-c]pyridines was prepared by acid-catalyzed cyclization of 1-aryl-2-[(2-thienylmethyl)amino]ethanol derivatives. The compounds were examined for their antidepressant activity, as demonstrated by their ability to inhibit the uptake of norepinephrine (NE) and serotonin (5-HT) and to prevent tetrabenazine-induced ptosis (TBZ) in mice. Significant inhibition of both neurotransmitters is observed for several of the tested compounds, while some of them are selective inhibitors of either NE or 5-HT uptake. Optimal activity is associated with the introduction of lipophilic substituents into the 4-position of the phenyl ring and less lipophilic substituents into the 2-position of the thiophene ring (11, 23). Compound 33 bearing substituents in positions 2 and 6 of the phenyl ring is inactive. This might be a consequence of an out of plane conformation of this compound.
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PMID:Synthesis and antidepressant activity of 4-aryltetrahydrothieno[2,3-c]pyridine derivatives. 647 Oct 69

Leaf and bark extracts of Byrsonima crassifolia displayed concentration-dependent, spasmogenic effects on rat fundus in vitro and biphasic effects on rat jejunum and ileum in vitro. Dose-related in vivo effects in intact rats using hippocratic screening were: decrease in motor activity, mild analgesia, back tonus, enophthalmos, reversible palpebral ptosis, ear blanching, Robichaud positive, catalepsy (awake) and strong hypothermia. Rat fundus in vitro was used as the bioassay to carry out an activity-directed separation. Bioactive material was concentrated in a 2% acetic acid leaf extract (HOAcE). Potency of HOAcE was increased by the presence of pargyline in the bathing solution. HOAcE was antagonized noncompetively by 1(1-naphthyl) piperazine (1-NP) and cyproheptadine and antagonized competitively by atropine (ATR). Cumulative concentration-response curves of HOAcE and serotonin (5-HT) did not show significant departure from parallelism (P > 0.1) and 5-HT potency was 6040 times that of HOAcE (95% confidence limits: 4620-7850). Solvent extraction of HOAcE split the spasmogenic activity of HOAcE into two types: (i) high-efficacy, low-potency, n-butanol-extracted, pargyline- and 1-NP-sensitive, ATR-insensitive activity, and (ii) low-efficacy, high-potency, ethyl acetate-extracted, pargyline-insensitive, ATR- and 1-NP-sensitive activity. HOAcE lacked muscarinic and nicotinic effects on rat jejunum and frog rectus abdominis. Results suggest the presence of more than one spasmogenic compound in the plant.
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PMID:Pharmacological and chemical screening of Byrsonima crassifolia, a medicinal tree from Mexico. Part I. 841 47


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