piperidines and Blepharoptosis

The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine, produces rapid and enduring antidepressant effect in patients with treatment-resistant depression. Similar dramatic effects have not been observed in clinical trials with other NMDAR antagonists indicating ketamine may possess unique pharmacological properties. Tetrabenazine induces ptosis (a drooping of the eyelids), and the reversal of this effect, attributed to a sympathomimetic action, has been used to detect first-generation antidepressants, as well as ketamine. Because the actions of other NMDAR antagonists have not been reported in this measure, we examined whether reversal of tetrabenazine-induced ptosis was unique to ketamine, or a class effect of NMDAR antagonists.. The effects of ketamine and other NMDAR antagonists to reverse tetrabenazine-induced ptosis were examined and compared with their antidepressant-like effects in the tail suspension test (TST) in mice.. All the NMDAR antagonists tested produced a partial reversal of tetrabenazine-induced ptosis and, as expected, reduced immobility in the TST. Ketamine, memantine, MK-801 and AZD6765 were all about half as potent in reversing tetrabenazine-induced ptosis compared to reducing immobility in the TST, while an NR2B antagonist (Ro 25-6981) and a glycine partial agonist (ACPC) were equipotent in both tests.. The ability to reverse tetrabenazine-induced ptosis is a class effect of NMDAR antagonists. These findings are consistent with the hypothesis that the inability of memantine, AZD6765 (lanicemine) and MK-0657 to reproduce the rapid and robust antidepressant effects of ketamine in the clinic result from insufficient dosing rather than a difference in mechanism of action among these NMDAR antagonists.

Topics: Adrenergic Uptake Inhibitors; Animals; Antidepressive Agents; Blepharoptosis; Disease Models, Animal; Drug Evaluation, Preclinical; Excitatory Amino Acid Antagonists; Hindlimb Suspension; Ketamine; Male; Mice; Mice, Inbred C57BL; Motor Activity; Phenethylamines; Phenols; Piperidines; Pyridines; Pyrimidines; Receptors, N-Methyl-D-Aspartate; Tetrabenazine

Nomifensine and three selected compounds from the series of H4a,H5-trans,H4a,H9b-cis-2,3,4,4a,5,9b-hexahydro-1H-in deno[1,2-b]pyridines have been resolved into their enantiomers. All compounds exhibit pronounced enantioselective activity with respect to their inhibition of tetrabenazine-induced ptosis and potentiation of yohimbine toxicity. Nomifensine exhibits the same preference for one enantiomer with respect to dopamine and norepinephrine reuptake, whereas in the indeno[1,2-b]pyridine series in vitro experiments do not discriminate between the optical antipodes. The absolute stereochemistry of the pharmacologically active enantiomers in both series was determined by X-ray analyses and comparative CD spectra. For biological activity the diphenylmethane is an essential structure feature in both series. Its absolute configuration proved to be 4S for nomifensine and 5S for indenopyridines. The similar pharmacological profile of the two chemical entities is therefore reflected in an identical configuration of this pharmacologically important molecular part.

Topics: Animals; Blepharoptosis; Brain; Chemical Phenomena; Chemistry; Dopamine; Drug Synergism; Indans; Indenes; Isomerism; Male; Mice; Molecular Conformation; Nomifensine; Norepinephrine; Piperidines; Rats; Serotonin; Structure-Activity Relationship; Synaptosomes; Tetrabenazine; Yohimbine

The 3-[(2-ethoxyphenoxy)methyl]piperidine derivatives 3-5 were synthesized and screened as potential antidepressant agents by the reserpine interaction test in mice and the evaluation of reuptake inhibition of biogenic amines in pig brain synaptosomal fractions. In addition, their anticonvulsant activity, tested by pentyleneetrazole antagonism, and approximate acute toxicity were evaluated. In vivo and in vitro tests showed that compounds 3 and 5 possess a biological activity comparable to that of the antidepressant drug viloxazine.

Topics: Animals; Antidepressive Agents; Blepharoptosis; Brain; Desipramine; Dopamine; Drug Evaluation, Preclinical; Ethyl Ethers; Hypothermia; Indicators and Reagents; Mice; Norepinephrine; Phenyl Ethers; Piperidines; Reserpine; Seizures; Serotonin; Structure-Activity Relationship; Synaptosomes; Viloxazine

A previously described series of 1-arylspiro[indoline-3,4'-piperidine]s was reported by us to possess significant antidepressant properties. This biological activity was found to be at a maximum among those compounds bearing an ortho substituent (e.g., NH2 as in 1) in the pendant aryl ring. In order to explore further this "ortho effect", we synthesized cyclic analogues of type 3 and 4 in which the position of the o-NH2-substituted aryl group is conformationally restricted and defined. When tested for antidepressant activity by tetrabenazine ptosis prevention in mice, it was found that restriction of rotation of the pendant o-aminophenyl group in these rigid analogues resulted in a loss of antidepressant properties. However, analgesic activity was retained and even improved by this molecular constraint.

Topics: Animals; Antidepressive Agents; Benzodiazepines; Biological Assay; Blepharoptosis; Indicators and Reagents; Magnetic Resonance Spectroscopy; Piperidines; Rats; Spectrophotometry, Infrared; Spiro Compounds; Structure-Activity Relationship; Tetrabenazine

A series of 1-arylspiro[indoline-3,4'-piperidine]s was synthesized and evaluated for potential antidepressant activity by tetrabenazine (TBZ) ptosis prevention and potentiation of 5-hydroxytryptophan (5-HTP) induced head twitching in pargyline-pretreated rats. Marked TBZ activity was observed with analogues bearing an ortho substituent on the pendant aromatic ring, as exemplified by lead compound 25a, 1-(2-chlorophenyl)spiro[indoline-3,4'-piperidine], which was also very active in potentiating 5-HTP stereotypy and yohimbine toxicity, as well as in inhibiting the muricidal behavior in rats. The potent in vivo activity of 25a, coupled with weak to moderate in vitro activity with respect to the blockade of neuronal reuptake of biogenic amines, seems to suggest a profile atypical of tricyclic antidepressants.

Topics: 5-Hydroxytryptophan; Animals; Antidepressive Agents; Biological Assay; Blepharoptosis; Drug Synergism; Humans; Indicators and Reagents; Indoles; Piperidines; Stereotyped Behavior; Structure-Activity Relationship; Tetrabenazine

A series of 3-aryl-1,3-dihydrospiro[benzo[c]thiophene-1,4'-piperidine] derivatives was synthesized and evaluated pharmacologically for potential psychotropic activity. Potent antidepressant-like activity was noted throughout the series, as assessed by tetrabenazine (TBZ) ptosis prevention in mice and potentiation of 5-hydroxytryptophan (5-HTP) induced behavioral effects in rats. A possible therapeutic advantage of the title compounds appears to be the overall low anticholinergic potential in comparison with the classic tricyclic antidepressants. Several congeners with nuclear halogen substitution also exhibited CNS stimulant properties, as evidenced by their ability to induce a dopamine agonist-like stereotypy and to increase the spontaneous motor activity in mice.

Topics: 5-Hydroxytryptophan; Animals; Antidepressive Agents, Tricyclic; Blepharoptosis; Chemical Phenomena; Chemistry; Drug Synergism; Male; Mice; Physostigmine; Piperidines; Spiro Compounds; Tetrabenazine

The interaction between neuroleptics and an anticholinergic, biperiden, in the antiavoidance, catalepsy and ptosis tests was investigated in mice for the purpose of predicting the extrapyramidal side-effects of neuroleptics. The cataleptic effect of most neuroleptics used was antagonized to some extent by biperiden, while the ptotic effect was hardly influenced. The antiavoidance effect of haloperidol, trifluperidol and perphenazine was markedly antagonized and that of chlorpromazine moderately. However, the effect of thioridazine, chlorprothixene, levomepromazine and clozapine was little antagonized. In neuropharmacological tests, haloperidol, trifluperidol and perphenazine exhibited a selective antidopaminergic activity, while chlorprothixene, levomepromazine and clozapine showed antidopaminergic, antiadrenergic and also anticholinergic activities when similar doses were given. These results indicate that biperiden antagonism may be marked in the tests related to the extrapyramidal symptoms and in drugs liable to induce extrapyramidal side effects, however, there would be little or no antagonism in drugs possessing the anticholinergic property and eliciting few extrapyramidal side-effects.

Topics: Animals; Antipsychotic Agents; Apomorphine; Avoidance Learning; Biperiden; Blepharoptosis; Catalepsy; Dopamine Antagonists; Drug Interactions; Humans; Male; Mice; Norepinephrine; Oxotremorine; Piperidines

The synthesis and antitetrabenazine activity of a series of N-heteroatom derivatives of 3-phenylspiro[isobenzofuran-1,4'-piperidines] are reported. Optimal antitetrabenazine activity is associated with compounds containing a sterically unhindered, basic nitrogen. Hydroxylamines 6, 11, 12, and 13 possess the most significant activity with ED50's of 1.4, 3.5, 4.7, and 4.0, respectively.

Topics: Animals; Antidepressive Agents; Benzofurans; Blepharoptosis; Methods; Mice; Piperidines; Structure-Activity Relationship; Tetrabenazine

Neuropharmacological properties of penfluridol (TLP-607) were investigated in experimental animals and were compared with those of haloperidol and chlorpromazine. Locomotor activity of mice significantly decreased at doses of 16-32 mg/kg p.o. Like haloperidol and chlorpromazine, TLP-607 (4-16 mg/kg p.o.) demonstrated catalepsy lasting for 48-72 hr in rats. TLP-607 strongly inhibited apomorphine-induced emesis in dogs and the ED50 was 0.016 mg/kg p.o. This effect lasted for 192 hr when administered 0.04 mg/kg p.o. TLP-607 antagnonized methamphetamine-induced stereotyped behavior in rats, and the ED50 was 1.83 ng/kg p.o. TLP-607 also inhibited conditioned avoidance responses in rats, and the ED50's in the pole climbing and Sidman avoidance methods were 6.73 and 3.4 mg/kg p.o., respectively. TLP-607 neither inhibited motor coordination nor enhanced hexobarbital-induced anesthesia in mice. These results suggest that TLP-607 is a potent and long-acting antipsychotic drug which has less neurotoxic side-effects.

Topics: Agonistic Behavior; Animals; Apomorphine; Avoidance Learning; Blepharoptosis; Body Temperature; Catalepsy; Cats; Central Nervous System; Chlorpromazine; Conditioning, Classical; Cooperative Behavior; Dogs; Dose-Response Relationship, Drug; Drug Synergism; Female; Haloperidol; Haplorhini; Hexobarbital; Humans; Locomotion; Male; Methamphetamine; Mice; Parasympatholytics; Penfluridol; Piperidines; Rats

Clopimozide (R 29 764), 5-chloro-1-(4-[4,4-bis(p-fluorophenyl)butyl]-4-piperidyl)-2-benzimidazolinone, is a new member of the potent and long-acting series of diphenylbutylpiperidine neuroleptics of which pimozide is the prototype, In animals the pharmacological profile of R 29 764 resembles that of typical neuroleptic compounds. R29 764 is very potent by oral route and has an extremely long duration of action. The onset of action of clopimozide is relatively fast, it is already very potent after 4 h and, in the procedures described, reaches its peak effect 24 h after administration. In spite of the high potency and long duration of action clopimozide is relatively atoxic. The safety margin, calculated as the ratio between the acute LD50 value and the lowest ED50 value is larger than or equal to 15.000 in rats and greater than 7.250 in dogs. Qualitatively, R 29 764 is more closely related to haloperidol, pimozide and penfluridol than to chlorpromazine. The side effect liability is expected to be very low, when hypotensive, autonomic and undesirable neurological side effects are concerned.

Topics: Animals; Apomorphine; Avoidance Learning; Behavior, Animal; Benzimidazoles; Blepharoptosis; Body Temperature Regulation; Body Weight; Catalepsy; Dextroamphetamine; Dogs; Escape Reaction; Female; Guinea Pigs; Haloperidol; Humans; Lethal Dose 50; Male; Mice; Norepinephrine; Penfluridol; Pimozide; Piperidines; Rats; Self Stimulation; Stereotyped Behavior; Tranquilizing Agents

Topics: Acridines; Animals; Behavior, Animal; Blepharoptosis; Central Nervous System; Dibenzoxepins; Dose-Response Relationship, Drug; Male; Mice; Motor Activity; Phenothiazines; Piperidines; Rats; Receptors, Drug; Structure-Activity Relationship; Thioxanthenes; Tranquilizing Agents; Xanthenes

Topics: Animals; Antidepressive Agents; Avoidance Learning; Benperidol; Blepharoptosis; Butyrophenones; Catalepsy; Chlorpromazine; Escape Reaction; Female; Fluorine; Fluphenazine; Haloperidol; Humans; Noise; Perphenazine; Piperidines; Rats; Spiro Compounds; Thioridazine; Tranquilizing Agents; Trifluoperazine; Triflupromazine

Topics: Animals; Antidepressive Agents; Avoidance Learning; Benperidol; Blepharoptosis; Butyrophenones; Catalepsy; Chlorpromazine; Depression, Chemical; Electroshock; Escape Reaction; Extinction, Psychological; Female; Fluorine; Haloperidol; Humans; Piperidines; Rats; Reinforcement, Psychology; Time Factors; Tranquilizing Agents; Trifluperidol