piperidines and talipexole

1. Antagonistic properties of OPC-28326 ([4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-propionyl-aminobenzoyl)] piperidine hydrochloride monohydrate), a selective peripheral vasodilator, were investigated by analysing the data from functional studies in various tissues from the rat and binding studies of the drug to alpha(2)-adrenoceptor subtypes. 2. Using a human recombinant receptor and rat kidney cortex, we found that OPC-28326 displays affinities to alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptors with K(i) values of 2040, 285, and 55 nM, respectively. The K(i) values of yohimbine for alpha(2A)-, alpha(2B)-, and alpha(2C)-adrenoceptors were 3.0, 2.0 and 11.0 nM, respectively. 3. B-HT 920, an alpha(2)-adrenoceptor agonist, produced a pressor response via peripheral postsynaptic alpha(2)-adrenoceptor stimulation (thought to be an alpha(2B)-subtype) in a reserpine-pretreated pithed rat preparation. OPC-28326 (3 - 30 mg kg(-1), i.v.) and yohimbine (0.3 - 3 mg kg(-1), i.v.) caused dose-dependent rightward shift in the pressor dose-response curve induced by B-HT 920. The apparent pA(2) values were 1.55 (0.87 - 2.75, 95% confidence interval) and 0.11 (0.06 - 0.21) mg kg(-1), respectively. The potency of OPC-28326 was about 14 times less than that of yohimbine. 4. Clonidine inhibited the tension developed by electrical stimulation, of the rat vas deferens, by its peripheral presynaptic alpha(2A/D)-adrenoceptor action. OPC-28326 (1 - 100 microM) and yohimbine (10 - 1000 nM) caused a rightward shift in the concentration-response curve of clonidine. The pA(2) values were 5.73 (5.54 - 5.91) and 7.92 (7.84 - 8.01), respectively, providing evidence for a potency of OPC-28326 of about 155 times less than that of yohimbine. 5. Mydriasis was induced by brimonidine via stimulation of central alpha(2A/D)-adrenoceptors in anaesthetized rats. Intravenous OPC-28326 had no effect on this action, even at a very high dose of 10 mg kg(-1) i.v., while yohimbine (0.1 - 0.3 mg kg(-1) i.v.) inhibited mydriasis in a dose-dependent manner, indicating that OPC-28326 was at least 100 times less potent than yohimbine in regard to the anti-mydriatic effect. 6. These data suggest that OPC-28326 preferentially exerts peripheral and postsynaptic antagonistic actions on the alpha(2B)- and alpha(2C)-adrenoceptor subtypes.

Topics: Adrenergic alpha-Antagonists; Aniline Compounds; Animals; Azepines; Binding, Competitive; Blood Pressure; Brimonidine Tartrate; Decerebrate State; Dose-Response Relationship, Drug; In Vitro Techniques; Male; Muscle Contraction; Mydriasis; Piperidines; Quinoxalines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Synaptic Transmission; Vas Deferens; Vasodilator Agents; Yohimbine

The present experiments were performed to examine the behavioral effects of OPC-14597, which acts on dopamine receptors in rats. OPC-14597 administered subcutaneously (SC) at doses of 0.1-5 mg/kg elicited yawning, as did OPC-4392 (0.5-2 mg/kg, SC) and (-)-3-PPP (2.5-10 mg/kg, SC). These yawning responses were blocked by intraperitoneal (IP) pretreatment with haloperidol (0.5 mg/kg) but were increased by pindolol (20 mg/kg, IP) or reserpine (5 mg/kg, IP), which per se did not elicit yawning. The yawning induced by talipexole, a selective dopamine D2 receptor agonist, was inhibited by OPC-14597 (0.5-5 mg/kg, SC) and (-)-3-PPP (10 mg/kg, SC). Apomorphine (0.5 mg/kg, SC), a dopamine D1/D2 receptor agonist, elicited stereotypy such as sniffing and licking but OPC-14597 (5-20 mg/kg, SC) did not induce this behavior. The stereotypy induced by apomorphine was inhibited not only by haloperidol (0.5 mg/kg, IP) and (-)-3-PPP (10 mg/kg, SC) but also by OPC-14597 (5-20 mg/kg, SC), without being affected by OPC-4392 (2 mg/kg, SC). In 6-hydroxydopamine (6-OHDA)-treated rats, apomorphine (0.5 mg/kg, SC) elicited rotation behavior whereas OPC-14597, OPC-4392 and (-)-3-PPP did not produce this behavior. These findings suggest that OPC-14597 provokes yawning without causing stereotypy and rotation but markedly antagonizes the talipexole-induced yawning and apomorphine-induced stereotypy, and that OPC-14597 thus exerts partial agonistic effects on yawning behavior but antagonistic effects on stereotypy in rats.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Azepines; Dopamine Agonists; Drug Synergism; Male; Oxidopamine; Piperazines; Piperidines; Quinolones; Rats; Rats, Wistar; Receptors, Dopamine; Stereotyped Behavior; Sympathectomy, Chemical; Yawning

The potencies for in vivo inhibition of substantia nigra pars compacta dopamine single cell firing were determined for apomorphine, BHT 920, N-0923, (+/-)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT), (+)-3-(3-hydroxyphenyl)-N-propylpiperidine (3-PPP), pramipexole, quinelorane, quinpirole, RU 24926, U-86170, and U-91356. Significant correlation was obtained between the potencies of these 11 highly efficacious dopamine receptor agonists and the in vitro binding affinities at dopamine D3 receptors, but not at dopamine D2L receptors. These results support a functional role for the dopamine D3 receptor subtype in the autoreceptor-mediated regulation of dopamine cell activity, while a role for dopamine D2 receptors awaits further analysis. In addition, the results demonstrate the limitations of using currently available dopamine receptor agonists to delineate relative in vivo roles for the dopamine D2 and D3 receptor subtypes.

Topics: Aminoquinolines; Animals; Apomorphine; Azepines; Benzothiazoles; Binding, Competitive; CHO Cells; Cricetinae; Dopamine Agonists; Dose-Response Relationship, Drug; Ergolines; Imidazoles; Male; Neurons; Phenethylamines; Piperidines; Pramipexole; Quinolines; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D3; Structure-Activity Relationship; Substantia Nigra; Tetrahydronaphthalenes; Thiazoles; Thiophenes; Transfection

Previous studies used either racemic 3-(3-hydroxyphenyl)-N-n-propylpiperidine [(+/-)-3-PPP] or lower doses of the mixed dopamine (DA) D1/D2 agonist apomorphine (APO) to conclude that brain DA D2 autoreceptors are not behaviorally functional until 28 days of age. The purpose of this study was to provide behavioral evidence for functional D2 autoreceptors before 28 days of age using DA agonists with greater selectivity for D2 autoreceptors. The locomotor activity of 10-, 21-, 35-day-old and adult rats was monitored after injection of a D2 autoreceptor agonist. There were significant decreases in the locomotor activity of 21-, 35-day-old, and adult rats injected with (-)-3-PPP, SND 919, or PD 128483. Lower doses of APO significantly decreased the activity of adult and 35-day-old rats but not younger rats. The only significant effect on the locomotor activity of 10-day-old rats was an increase in activity after injection of APO, 0.01 mg/kg or higher, or B-HT 920, 0.01 mg/kg. The results suggest that brain DA D2 autoreceptors are behaviorally functional at 21, but not 10, days of age.

Topics: Aging; Aminoquinolines; Animals; Apomorphine; Azepines; Behavior, Animal; Benzothiazoles; Dopamine Agonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Male; Motor Activity; Piperidines; Pramipexole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Thiazoles

In male rats, a high dose of the alkylating compound N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 30 mg/kg s.c., 24 h) caused a reduction of pituitary dopamine D2 receptor density by 27% as measured by means of in vivo radioligand binding (using a single dose of the ligand [3H]spiperone). The same dose of EEDQ reduced the potency, but not the maximal response, of the dopamine D2 receptor agonists R-(-)-N-n-propylnorapomorphine (NPA), (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((+)-3-PPP), and 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5]azepine (B-HT 920) with respect to suppression of prolactin release after pretreatment with gamma-butyrolactone. The measured reduction in dopamine D2 receptor density after EEDQ was of the same magnitude as the reduction in receptor number predicted from the EEDQ induced shift in the dose-response curve of the full dopamine D2 receptor agonist NPA. The findings are discussed in relation to our previous observation that a somewhat lower dose of EEDQ (20 mg/kg s.c., 24 h) effectively reduces the efficacy of partial dopamine D2 receptor agonists while affecting neither the prolactin response to full dopamine D2 receptor agonists nor the density of pituitary dopamine D2 receptors.

Topics: Animals; Azepines; Dopamine Agents; Male; Piperidines; Pituitary Gland; Prolactin; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2

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

SND 919 [S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole) is expected to have a potent and selective dopamine D2-receptor agonistic activity. From this information, the present study was performed to investigate effects of SND 919 on yawning behavior and prolactin secretion in rats. Subcutaneous injections of SND 919 (25-500 micrograms/kg, s.c.) elicited yawning responses. Its dose-response curve was bell-shaped with maximal effects at a dose of 100 micrograms/kg. Yawning behavior was also evoked by the putative dopamine autoreceptor agonists, talipexole (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d]azepine) (B-HT 920) (5-100 micrograms/kg, s.c.) and (+)-3-PPP ((+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine) (5-15 mg/kg, s.c.). The yawning induced by SND 919 (100 micrograms/kg, s.c.) as well as talipexole (25 micrograms/kg, s.c.) was inhibited by pretreatment with dopamine D2-receptor antagonists such as spiperone (0.5 mg/kg, i.p.) and YM-09151-2 (cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-met hylamino- benzamide) (0.1 mg/kg, i.p.), or the muscarinic receptor antagonist, scopolamine (0.5 mg/kg, i.p.). However, the yawning was not affected by the dopamine D1-receptor antagonist, SCH 23390 (R(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-o l) (0.5 mg/kg, i.p.). Stereotypy such as licking and biting was not observed following the administration of SND 919, talipexole and (+)-3-PPP. Administration of SND 919, talipexole or (+)-3-PPP in respective yawn-inducing doses caused a reduction in both the basal prolactin levels and the alpha-methyl-p-tyrosine-induced hyperprolactinemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: alpha-Methyltyrosine; Animals; Azepines; Behavior, Animal; Benzothiazoles; Dopamine Agents; Male; Methyltyrosines; Piperidines; Pramipexole; Prolactin; Rats; Rats, Inbred Strains; Receptors, Dopamine; Thiazoles; Yawning

Using the technique of brain dialysis in freely moving rats we have investigated the effect of various dopamine (DA) receptor agonists on the release and metabolism of DA in two terminal dopaminergic areas, the nucleus accumbens and the dorsal caudate. Low doses of various DA receptor agonists such as apomorphine (12-100 micrograms/kg s.c.), LY 171555 (5-50 micrograms/kg s.c.), pergolide (5-25 micrograms/kg s.c.), (+)-3PPP (0.5-2.5 mg/kg s.c.) and BHT 920 (10-250 micrograms/kg s.c.) reduce DA release and elicit hypomotility. The potency of the drugs and their effectiveness is similar in the two areas. Inhibition of DA release appears related to the ability of the various agonists to stimulate D-2 rather than D-1 receptors. Thus, the reportedly selective D-1 agonist, SKF 38393, was inactive on DA release and metabolism even at doses fully active in eliciting D-1-mediated effects (grooming); on the other hand apomorphine, a D-1/D-2 agonist, and pergolide, a D-2 agonist with rather weak D-1 activity, reduced DA release in a manner which was related to their agonist activity at D-2 receptors; finally LY 171555, (+)-3PPP and BHT 920, which selectively stimulate D-2 receptors, were fully active at reducing DA release in vivo. Apomorphine, pergolide, LY 171555 and (+)-3PPP given at higher doses elicited behavioral stimulation. In contrast, BHT 920 failed to do so. In further contrast (-)-3PPP (0.1-10 mg/kg s.c.), which failed to reduce DA release at low doses, actually stimulated it at high doses (10 mg/kg s.c.) and elicited hypomotility, thus resembling DA receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; 3,4-Dihydroxyphenylacetic Acid; Animals; Apomorphine; Azepines; Behavior, Animal; Benzazepines; Brain; Dialysis; Dopamine; Ergolines; Homovanillic Acid; Isomerism; Male; Motor Activity; Neurons; Pergolide; Piperidines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Time Factors

Low doses of BHT 920, LY 171555 and (+)3PPP, three dopamine agonists selective for D-2 receptors, induced yawning in rats. This effect was reduced by the selective D-1 antagonist SCH 23390 but the antagonism did not exceed a 50% reduction from the control values. In contrast, the selective D-2 antagonist (-)sulpiride completely abolished agonist-induced yawning. A 6 h reserpine pretreatment (5 mg/kg i.p.), which depletes brain dopamine (DA) by about 95%, reduced agonist-induced yawning by an extent similar to SCH 23390; in the reserpinized rats, SCH 23390 completely lost the property of blocking agonist-induced yawning while (-)sulpiride retained it. Two 5HT receptor antagonist, ketanserin and metergoline failed to influence agonist-induced yawning. The reportedly selective D-1 agonist, SKF 38393, failed to induce yawning in normal rats as well as in rats pretreated with reserpine 6 or 16 h earlier. If one excludes that SCH 23390 and the D-2 agonists interact with the same DA-receptors, the data are consistent with the possibility that stimulation of D-1 receptors by endogenous DA plays a permissive-facilitatory role for the behavioural expression of D-2 receptor activation.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Adrenergic alpha-Agonists; Animals; Azepines; Benzazepines; Brain Chemistry; Dopamine; Ergolines; Kainic Acid; Ketanserin; Male; Metergoline; Piperidines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reserpine; Sulpiride; Yawning

Possible involvement of central alpha-2 adrenoceptors in the hypertensive response to i.c.v. injected clonidine was investigated in free-moving, normotensive rats. Clonidine (2-50 micrograms) injected i.c.v. produced a dose-dependent and long-lasting pressor response associated with bradycardia in conscious rats, but a long-lasting depressor response in anesthetized rats. The pressor response to clonidine (20 micrograms i.c.v.) was antagonized in a dose-dependent manner by central (i.c.v.) pretreatment with yohimbine (20-100 micrograms) and was abolished by a high dose (100 micrograms), whereas the same dose of yohimbine injected i.v. had less effect on the response. Central pretreatment with prazosin (10 and 20 micrograms) inhibited, but did not abolish, the pressor response to clonidine. However, systemic (i.v.) pretreatment with the same dose of prazosin (10 and 20 mu) was more effective in reducing the clonidine-induced pressor response than central pretreatment with the drug. The pressor response to clonidine (20 micrograms i.c.v.) was not significantly modified by central pretreatment with pyrilamine (50 and 100 micrograms), cimetidine (50 and 100 micrograms), ketanserin (50 and 100 micrograms) or procaine (100 micrograms). The selective alpha-2 adrenoceptor agonist, BHT-920, injected i.c.v. (5-50 micrograms) also produced a dose-dependent pressor response which was abolished by either anesthesia or central pretreatment with yohimbine, but not with prazosin, whereas the selective alpha-1 adrenoceptor agonist, methoxamine (10-100 micrograms i.c.v.), caused a slight increase in mean blood pressure only at higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Azepines; Blood Pressure; Brain; Cimetidine; Clonidine; Hydroxydopamines; Injections, Intraventricular; Ketanserin; Male; Methoxamine; Oxidopamine; Piperidines; Prazosin; Procaine; Pyrilamine; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Yohimbine

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Azepines; Female; Male; Phenanthrenes; Piperidines; Prolactin; Rats; Rats, Inbred Strains; Receptors, Dopamine; Tetrahydronaphthalenes

Rat striatal synaptosomal tyrosine hydroxylation was inhibited dose- and pH dependently by a number of dopamine agonists. The catecholic agonists apomorphine and (-)N-n-propylnorapomorphine inhibited synaptosomal tyrosine hydroxylase completely, with IC50 values of around 0.3 mumol/l at pH 6.6. The noncatechol agonists pergolide and bromocriptine and the putative dopamine autoreceptor agonists 3-PPP(-), 3-PPP(+), HW-165 and B-HT 920 produced only partial inhibition of synaptosomal tyrosine hydroxylation at high concentrations. Comparison of the inhibition of synaptosomal and soluble tyrosine hydroxylase indicated that the inhibition produced by apomorphine could be ascribed to a direct effect on the enzyme, whereas this was not the case for the noncatechol agonists. The inhibition produced by pergolide and 3-PPP(-) was not antagonised by either dopamine receptor or alpha-adrenoceptor antagonists. The present results have been compared with results reported in the literature for inhibition of synaptosomal tyrosine hydroxylation and for two other tests of dopamine autoreceptor agonist activity (inhibition of dopamine release from striatal slices in vitro, and inhibition of the gamma-butyrolactone induced increase in dopamine synthesis in vivo). It is concluded that inhibition of striatal synaptosomal tyrosine hydroxylation by dopamine agonists does not fulfil the criteria required for it to be considered as a useful measure of dopamine autoreceptor function.

Topics: Adrenergic alpha-Agonists; Animals; Apomorphine; Azepines; Corpus Striatum; Depression, Chemical; Dopamine; Ergolines; Hydrogen-Ion Concentration; In Vitro Techniques; Male; Pergolide; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Neurotransmitter; Synaptosomes; Tyrosine 3-Monooxygenase