piperidines and dironyl

In a companion article, we extensively reviewed the pharmacological actions of the enantiomers of the dopamine analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP. The profiles of action exhibited by transdihydrolisuride (TDHL) and the trans-fused 7-OH-1,2,3,4,4a,5,6,10-octahydrobenzo(f)quinoline (HW 165) were also described. These latter agents, along with (-)-3-PPP, exert a variety of effects at different DA receptors depending on the anatomical location of these receptor sites and the experimental conditions. In the first part of the present article, it is suggested that the intrinsic activity of these agents in different pharmacological models is dependent on the responsiveness of the relevant DA-receptors which, in turn, is related to the degree of previous agonist occupancy of these sites. In situations where these agents exhibit partial agonist activity, their pharmacological effect is also dependent on the relative concentrations of drug and endogenous DA competing for common receptor sites. A number of theoretical implications will be discussed relevant to the suggestion that DA receptors exist in various adaptational states which can influence drug action. In the second part of this review, we will consider the behavioural profile exhibited by (-)-3-PPP in relation to that observed with classical DA antagonists. In addition, the potential clinical application of (-)-3-PPP and similar-acting agents will be discussed.

Topics: Animals; Antipsychotic Agents; Apomorphine; Behavior, Animal; Corpus Striatum; Cyclic AMP; Dextroamphetamine; Dopamine; Humans; Isomerism; Lisuride; Models, Neurological; Molecular Conformation; Motor Activity; Nucleus Accumbens; Piperidines; Pituitary Gland, Anterior; Prolactin; Rats; Receptors, Dopamine; Substantia Nigra; Synaptosomes

The behavioural, biochemical, neuroendocrinological and electrophysiological actions of the enantiomers of the dopamine (DA) analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, are extensively reviewed. (+)-3-PPP acts in a fashion similar to classical direct-acting DA agonists, stimulating both DA autoreceptors and postsynaptic DA receptors, although in some situations the drug appears to exhibit partial agonist activity. (-)-3-PPP exerts a variety of actions in different pharmacological models. Either agonistic, antagonistic or both agonistic and antagonistic activity are observed depending on the anatomical location of the relevant DA receptors and the experimental conditions. The actions of transdihydrolisuride (TDHL) and the trans-fused 7-OH-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinoline (HW 165) are also discussed. These agents possess a similar spectrum of action to (-)-3-PPP suggesting a new generation of DA agonists which exhibit variable intrinsic activity at different DA receptors. Finally, evidence is presented indicating that the 3-PPP enantiomers display selectivity for DA receptors.

Topics: Acetylcholine; Adenylyl Cyclases; Animals; Behavior, Animal; Brain; Caudate Nucleus; Deoxyglucose; Dopamine; Humans; Lisuride; Models, Biological; Nerve Tissue Proteins; Phenanthrenes; Piperidines; Rats; Receptors, Dopamine; Stereoisomerism; Substantia Nigra; Synaptosomes; Tegmentum Mesencephali

Aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP have been classified as dopamine D(2) receptor partial agonists based largely on their activity in second messenger-based assays of dopamine D(2) receptor signalling. Nevertheless, signal transduction amplification might result in these compounds behaving as dopamine D(2) receptor full agonists at a more downstream level of signalling. We compared the intrinsic activity (E(max), expressed as a percentage of the maximal effect of dopamine) of aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP using second (calcium (Ca(2+)) mobilization) and third (extracellular signal-regulated kinase 2 (ERK2) phosphoprotein expression) messenger readouts of cloned human dopamine D(2long) (hD(2L)) receptor signalling in CHO cells. These compounds were all less potent and displayed lower intrinsic activity in the Ca(2+) assay (aripiprazole = 24.3%, (+)terguride = 56.9%, OPC-4392 = 58.6% and (-)3-PPP = 75.1%), and aripiprazole (E(max) = 54.5%) displayed a substantially lower intrinsic activity than (+)terguride (E(max) = 92.3%), OPC-4392 (E(max) = 93.1%) and (-)3-PPP (E(max) = 101.1%) in the more downstream-based ERK2 phosphoprotein expression assay. These drug effects on Ca(2+) mobilization and ERK2 phosphoprotein expression were mediated through dopamine hD(2L) receptors, as they all were blocked by (-)raclopride, whereas (-)raclopride and other dopamine D(2) receptor antagonists (haloperidol, risperidone, ziprasidone, olanzapine, clozapine and quetiapine) were inactive on their own in both assays. These data are consistent with clinical evidence that only dopamine D(2) receptor partial agonists with a sufficiently low enough intrinsic activity will prove effective against the positive symptoms of schizophrenia, and also highlight the importance of using downstream-based assays in the discovery of novel D(2) receptor partial agonist therapeutics.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Calcium Signaling; CHO Cells; Cloning, Molecular; Cricetinae; Cricetulus; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Immunoblotting; Lisuride; MAP Kinase Signaling System; Microscopy, Confocal; Mitogen-Activated Protein Kinase 1; Phosphorylation; Piperazines; Piperidines; Quinolones; Raclopride; Receptors, Dopamine D2; Schizophrenia; Time Factors; Transfection

Aripiprazole is the first clinically approved atypical antipsychotic agent having dopamine D2 receptor partial agonist activities. To evaluate aripiprazole's agonist and antagonist properties, we established a Chinese hamster ovary cell line expressing high and low densities of the long and short isoforms of human dopamine D2 receptors, then compared its properties with 7-{3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy}-2(1H)-quinolinone (OPC-4392), S(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((-)-3-PPP), and terguride (other partial agonists) using forskolin-stimulated cAMP accumulation as an index. In cells expressing high receptor densities, all partial agonists predominantly behaved as agonists. However, in cells expressing low receptor densities, the partial agonists showed significantly lower maximal effects than dopamine. Aripiprazole showed the lowest intrinsic activities. In addition, all compounds blocked the action of dopamine with a maximum effect equal to that of each compound alone. Aripiprazole's low intrinsic activities may account for the clinical finding that, unlike the other partial agonists, it is substantially active against both positive and negative symptoms of schizophrenia.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Binding, Competitive; Cell Membrane; CHO Cells; Colforsin; Cricetinae; Cricetulus; Cyclic AMP; DNA, Complementary; Dopamine; Dopamine Agonists; Dopamine Antagonists; Haloperidol; Humans; Lisuride; Piperazines; Piperidines; Quinolones; Raclopride; Radioligand Assay; Receptors, Dopamine D2; Risperidone; Transfection; Tritium

Eight Cebus apella monkeys were treated with haloperidol for 2 years. Five monkeys had developed mild oral tardive dyskinesia and all were primed for neuroleptic induced dystonia, thus serving as a model for both chronic and acute extrapyramidal side effects. In this model, the partial dopamine D2 receptor agonists SDZ HDC-912, SDZ HAC-911, terguride, (-)-3-(3-hydroxyphenyl)-N-propylpiperidine) ((-)-3-PPP) and SND 919 were tested for extrapyramidal side-effect liability. Their antipsychotic potential was also tested, using a dose of dextroamphetamine producing mild stereotypy and moderate motoric unrest. For comparison, the dopamine D2 receptor agonist, LY 171555 and antagonist, raclopride were used. In contrast to the other drugs tested, SDZ HAC-911 consistently reduced oral activity, P < 0.05 (at doses from 0.005 to 0.025 mg/kg). The relative dystonic potencies were raclopride > SDZ HDC-912 > SDZ HAC-911 = terguride. Neither (-)-3-PPP nor SND 919 produced dystonia, but had observable dopamine D2 receptor agonistic effects, (-)-3-PPP producing emesis at 1-4 mg/kg and SND 919 producing motoric unrest and stereotypy at 0.05-0.25 mg/kg. Comparing the antiamphetamine effects of the more antagonist-like drugs with raclopride, the relative potencies were terguride = SDZ HAC-911 > SDZ HDC-912 > raclopride. Comparing the antiamphetamine effects of the more agonist-like drugs with LY 171555, the relative potencies were SND 919 > (-)-3-PPP > LY 171555 in relation to motoric unrest, while neither (-)-3-PPP nor LY 171555 produced inhibition of stereotypy.

Topics: Administration, Oral; Amphetamine; Animals; Antipsychotic Agents; Behavior, Animal; Benzothiazoles; Cebus; Disease Models, Animal; Dopamine Agents; Dopamine D2 Receptor Antagonists; Dyskinesia, Drug-Induced; Dystonia; Ergolines; Female; Haloperidol; Lisuride; Male; Piperidines; Pramipexole; Quinpirole; Raclopride; Salicylamides; Thiazoles

Previous work in this laboratory, as well as observations reported in the literature, indicate that the adrenal medulla contains dopamine (DA) receptors of the D-2 subtype, which among other things are capable of controlling the DA level in rat adrenal glands. To further characterize the DA receptors involved in the control of the adrenal DA level, the effects of 9 DA receptor agonists with various intrinsic activities were compared. After various periods of drug administration the rats were killed by decapitation and the DA content of the adrenal glands and the DOPAC content of the forebrain were measured by high-performance liquid chromatography with electrochemical detection. All the investigated DA receptors agonists caused an increase in adrenal DA level, although statistical significance was not reached in one case [(-)-HW 165]. Domperidone, a DA D-2 receptor antagonist which does not readily cross the blood brain barrier, blocked the DA-elevating effects of apomorphine, quinpirole, B-HT 920 and both enantiomers of 3-PPP. For the two ergolines terguride and SDZ 208-920 the blockade by domperidone was not complete, suggesting that their effects are mediated not only through DA, but also through other receptor systems. The dose of domperidone used (3 mg/kg) had but a marginal influence on brain DOPAC levels, supporting the almost exclusively peripheral effect of this agent. Our data indicate that the DA D-2 receptors which control the DA level in the adrenal medulla in rats, have characteristics similar to, though not identical with the autoreceptors in the forebrain.

Topics: 3,4-Dihydroxyphenylacetic Acid; Adrenal Medulla; Animals; Apomorphine; Azepines; Diencephalon; Domperidone; Dopamine; Dopamine Agents; Epinephrine; Ergolines; Lisuride; Male; Norepinephrine; Phenanthrenes; Piperidines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Telencephalon

The effects of partial D2 dopamine (DA) receptor agonists on the behavioural activation produced by 1.5 and 8.0 mg/kg d-amphetamine were compared with the changes produced by the classical DA antagonist haloperidol. Alterations in behaviour were assessed in standard activity monitoring cages by direct observation of the rats using a rapid time sampling procedure. Haloperidol blocked d-amphetamine (1.5 mg/kg)-induced increases in photocell counts, ambulation, rearing and sniffing up, and after the highest dose of the DA antagonist the animals were mainly inactive. The partial D2 DA agonist SDZ 208-911 was equipotent to haloperidol in blocking the increase in photocell counts and rearing produced by d-amphetamine. However, even high doses of the drug did not reduce the incidence of sniffing or induce inactivity, but qualitative changes in the form of sniffing did occur. Although considerably less potent, preclamol exerted similar effects to SDZ 208-911. The profiles of SDZ 208-912 and terguride were intermediary to those of SDZ 208-911 and haloperidol. All compounds blocked the repetitive sniffing down produced by 8.0 mg/kg d-amphetamine. After a low dose of haloperidol, these stereotyped behaviours were replaced by a behavioural syndrome similar to that observed with low dose d-amphetamine, but inactivity was observed following a further small increase in antagonist dose. The blockade of stereotypy by SDZ 208-911, preclamol and terguride was accompanied only by the low dose d-amphetamine behavioural syndrome; no inhibition of sniffing or induction of inactivity occurred. SDZ 208-912 exhibited a profile with features very similar to that noted with haloperidol. These findings suggest that partial D2 agonists exert similar, but not identical, behavioural effects to classical DA antagonists when dopaminergic function in increased by d-amphetamine. The differences in behavioural profile are discussed in relation to variations in the intrinsic efficacy of the dopaminergic compounds and to differences in the response capability of D2 receptor populations underlying the different behaviours produced by d-amphetamine.

Topics: Animals; Dextroamphetamine; Dopamine Agents; Dose-Response Relationship, Drug; Ergolines; Lisuride; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D2; Stereotyped Behavior

The effects of the enantiomers of 3-hydroxyphenyl-N-n-propylpiperidine (3-PPP) at dopamine (DA) synthesis modulating autoreceptors, measured as DOPA accumulation after decarboxylase inhibition, were assessed in vivo and in rat striatal slices. In vivo, (+)-3-PPP inhibited DOPA accumulation in the striatum, nucleus accumbens, and medial prefrontal cortex, whereas (-)-3-PPP either increased (striatal) or had no effect (accumbens, prefrontal cortex), on DOPA accumulation. In vitro, both (+)- and (-)-3-PPP reduced basal DOPA accumulation with a similar order of potency (apparent EC50 = 2.1 and 1.0 microns, respectively) and maximal effect, although they were less potent than the D2 DA receptor agonist quinpirole (EC50 = 0.15 microM). The inhibition of tyrosine hydroxylation was also observed in slices obtained from reserpine-pretreated rats and was blocked by the selective D2 DA antagonist (-)-sulpiride. This suggests that 3-PPP inhibition of DOPA accumulation was mediated directly by stimulation of DA D2 receptors. Increasing the amount of extracellular DA by depolarizing slices with 30 mM K+ did not alter the qualitative effects of either quinpirole or (+)-3-PPP. However, the stimulation of DA autoreceptors by (-)-3-PPP was no longer apparent under conditions of elevated extracellular DA. Under these depolarizing conditions, (-)-3-PPP actually antagonized the inhibitory effect afforded by either quinpirole or pergolide. A similar switch in profile was observed with transdihydrolisuride (TDHL). The data support the notion that (-)-3-PPP and TDHL are partial agonists at synthesis modulating DA autoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Biogenic Monoamines; Cerebral Cortex; Corpus Striatum; Dihydroxyphenylalanine; Dopamine; Electrochemistry; Ergolines; In Vitro Techniques; Lisuride; Male; Nerve Tissue Proteins; Nucleus Accumbens; Piperidines; Potassium; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereoisomerism

In a previous study we have demonstrated that repeated reserpine treatment markedly enhances the intrinsic activity of the partial dopamine (DA) agonist (-)-3-PPP (preclamol) on pituitary DA receptors in female rats. This effect was attributed to the DA-depleting action of reserpine. However, since reserpine may also decrease oestrogen secretion, and since this hormone is known to affect dopaminergic transmission, experiments with ovariectomized, oestrogen-replaced female rats were undertaken. Ovariectomized rats were administered a depot preparation of oestradiol valerate in a dose that, according to literature data, yields physiological or slightly supraphysiological plasma concentrations of oestrogen. In spite of this treatment, repeated reserpine administration was found to substantially increase the intrinsic activity of (-)-3-PPP, as well as that of the partial DA agonist TDHL (terguride), on female pituitary DA receptors. It was concluded that repeated reserpine treatment increases pituitary DA receptor responsiveness in female rats by depleting DA, rather than by decreasing oestrogen secretion.

Topics: Animals; Estradiol; Estrogens; Female; Lisuride; Ovariectomy; Piperidines; Pituitary Gland, Posterior; Radioimmunoassay; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reserpine

The abilities of the mixed agonists/antagonists on dopamine (DA) receptors, (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [-)-3-PPP) and transdihydrolisuride (TDHL), to suppress serum prolactin levels in acutely hyperprolactinemic male and female rats were investigated. gamma-Butyrolactone was used to deplete endogenous DA and raise serum prolactin concentrations. Both (-)-3-PPP and TDHL were found to cause sexually differentiated responses: (-)-3-PPP reduced serum prolactin levels dose dependently and effectively in males but caused only a modest decrease of prolactin release in females. Moreover, (-)-3-PPP antagonized the prolactin-suppressing effects induced by the DA receptor agonist (+)-3-PPP in females. Likewise TDHL decreased prolactin secretion markedly in males while it had only slight effects in females. It can be concluded from these results that the intrinsic activities of the partial DA agonists (-)-3-PPP and TDHL are lower in female than in male rats, suggesting a reduced responsiveness of hypophyseal DA receptors in females. Since DA levels in the pituitary portal circulation are higher in female than in male rats, this study gives further support to the hypothesis claiming an inverse relationship between the intrinsic activity of a mixed agonist/antagonist and the degree of previous stimulation of its receptor.

Topics: Animals; Antiparkinson Agents; Ergolines; Female; In Vitro Techniques; Lisuride; Male; Piperidines; Pituitary Gland; Prolactin; Rats; Rats, Inbred Strains; Receptors, Dopamine; Sex Factors; Stereoisomerism