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Biomedical subjects

S B Ross

Publications and source records attributed to S B Ross.

At least 55 records · Page 3Linked to original sources
PubMed1990

Different effects on the responses of functional pre- and postsynaptic 5-HT1A receptors by repeated treatment of rats with the 5-HT1A receptor agonist 8-OH-DPAT.

The effects of repeated treatment of rats with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 1.0 mg/kg, subcutaneously, twice daily for 7 days, on the stimulation of post- and presynaptic 5-HT1A receptors were examined. The postsynaptic responses, hypothermia and inhibition of the cage-leaving response, evoked by 0.05 mg/kg 8-OH-DPAT, were measured 48 hr after the final injection. Another postsynaptic response, the 5-HT syndrome (flat body posture and forepaw treading) was observed after the third injection of 8-OH-DPAT (1.0 mg/kg s.c.). One presynaptic response examined was the 8-OH-DPAT-induced decrease in the concentration of 5-hydroxyindoleacetic acid (5-HIAA), that indicates a decrease in turnover of 5-HT, due to stimulation of 5-HT receptors on the cell bodies and measured as the ratio of 5-HIAA to 5-HT in the hippocampus, hypothalamus and medulla oblongata. Another presynaptic response was the 8-OH-DPAT-induced decrease in the accumulation of 5-hydroxytryptophan (5-HTP) in the hippocampus and hypothalamus, after inhibition of L-aromatic amino acid decarboxylase by 3-hydroxybenzylhydrazine (NSD 1015), that is due to stimulation of autoreceptors on the 5-HT cell bodies. The kinetic properties of 5-HT1A receptors in the cerebral cortex and hippocampus, hippocampus alone, hypothalamus and medulla oblongata were determined with [3H]8-OH-DPAT. It was found that the postsynaptic effects were markedly attenuated after the treatment, the hypothermic effect already after a single dose.(ABSTRACT TRUNCATED AT 250 WORDS)

5-Hydroxytryptophan↗
PubMed1990

Further studies on the high-affinity binding of 3H-alaproclate to membranes from rat liver and some other tissues.

The high affinity binding of 3H-alaproclate to membranes in liver homogenates from naive rats and those treated with phenobarbital sodium, 75 mg/kg intraperitoneally, alaproclate hydrochloride, 40 mg/kg intraperitoneally proadifen hydrochloride, 40 mg/kg intraperitoneally once daily for 7 days and killed 24 hr after the last injection was examined. The treatment increased the normal number of alaproclate binding sites (Bmax: 1.1 nmol/g tissue, KD: 0.6 nM) by factors of about 10, 4 and 6, respectively. About 80% of the binding was localized to the microsomal fraction in both normal and phenobarbital treated rats. Ninety % of the alaproclate displaceable binding in a microsomal preparation of the normal liver was inhibited by low (nM) concentrations of proadifen whereas only about 20% in the liver preparations from phenobarbital treated rats was inhibited by low concentrations of proadifen. Thus, the main part of the induced binding sites was insensitive to proadifen. The same was found for the alaproclate and proadifen-induced alaproclate binding sites. The stereoselectivity of alaproclate enantiomers for binding to the normal and the induced binding sites was different: the S-(-) form was 100 times more potent than the R-(+)- enantiomer in inhibiting binding of racemic alaproclate to the normal sites, whereas the latter form was 3 times more potent than the former in inhibiting the binding to the phenobarbital-induced proadifen insensitive binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1990

Alpha 1 (but not alpha 2)-adrenoceptor agonists in combination with the dopamine D2 agonist quinpirole produce locomotor stimulation in dopamine-depleted mice.

Mice were premedicated with reserpine and alpha-methyl-p-tyrosine to deplete stores of dopamine (DA) (and other neurotransmitters) and to stop DA (and noradrenaline (NA] synthesis. In DA-depleted mice, the mixed alpha 1/alpha 2 agonist clonidine potentiated locomotor stimulation induced by a low dose of apomorphine as measured in automated activity cages. Clonidine and the slightly alpha 1-selective agonist ST587, but not ST91, an alpha-agonist which does not readily cross the blood brain barrier, produced marked stimulation when combined with the selective D2 agonist quinpirole. The D1 -selective agonist SKF38393 also produced marked excitation when combined with quinpirole. All the selective agonists, bar quinpirole which in some cases produced a significant locomotor stimulation, were relatively inactive when given alone. A "blind" observational analysis of the animals challenged with clonidine plus quinpirole indicated an increase in sniffing, rearing and shaking behaviour. In contrast, observation of the animals challenged with SKF38393 plus quinpirole indicated increased sniffing, rearing and biting and, in one case, increased grooming behaviour. Clonidine did not produce excitation (in automated cages) when combined with the selective D1 agonist SKF38393. The excitation produced by clonidine plus quinpirole was blocked by the selective D2 antagonist raclopride but not by the selective D1 antagonist SCH23390. The stimulation was also blocked by the alpha 1 antagonist prazosin but not by the alpha 2 antagonists idazoxan or yohimbine. Biochemical analysis in the striata of mice challenged with clonidine plus quinpirole did not provide any obvious biochemical basis for the behavioural interaction. It is concluded that alpha 1 receptor agonists in combination with D2 DA agonists can produce marked stimulation in DA depleted mice.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Dopamine D-2 receptor agonist-induced behavioural depression: critical dependence upon postsynaptic dopamine D-1 function. A behavioural and biochemical study.

The dopamine (DA) D-2 receptor agonists quinpirole (threshold dose, 0.01 mg/kg IP), pergolide (0.025 mg/kg), B-HT 920 (0.003 mg/kg) and (-)-3-PPP (4 mg/kg) produced dose-dependent locomotor depression (immobility) in mice as assessed by a subjective scoring system, with the immobility being characterized by a frozen posture. The animals were still but had their eyes open. The immobility was accompanied by reductions in sniffing, rearing and grooming. The depression (and the associated reduction in the various behaviours) produced by quinpirole (0.1 mg/kg), pergolide (0.1 mg/kg) and B-HT 920 (0.1 mg/kg) was substantially (but not always completely) reversed by the selective D-1 receptor agonist SKF38393 (up to 12 mg/kg) and the non-selective D-1 receptor agonist CY208243 (up to 3 mg/kg). The immobility induced by (-)-3-PPP (16 mg/kg) was also reversed by CY208243 and SKF38393, but the reversal was due to an increase in grooming behaviour in mice challenged with the D-1 receptor agonists, whether or not the animals had also received (-)-3-PPP. There was no reversal of the depression of rearing or sniffing. In contrast, CY208243 and SKF38393 also antagonized the immobility induced by B-HT 920, but the reversal was accompanied by at least partial reversals of the depression of sniffing, rearing and grooming. The reversal of quinpirole-induced immobility by SKF38393 and CY208243 was antagonized by SCH23390 (0.1 mg/kg). The selective D-2 receptor antagonist raclopride (0.025 to 0.4 mg/kg) could not reverse quinpirole-induced immobility. High doses of either raclopride (0.4 mg/kg) or SCH23390 (greater than 0.1 mg/kg) significantly increased immobility. Although raclopride itself (0.2 mg/kg) produced a substantial increase in DOPAC and homovanillic acid (HVA) levels in the striatum, it did not antagonize the autoreceptor mediated effects of quinpirole (0.1 mg/kg) in reducing the striatal dihydroxyphenylacetic acid (DOPAC) to DA ratio. However, the same dose of raclopride was partly effective in reducing the effects of lower doses of quinpirole (0.01 and 0.03 mg/kg) on the striatal DOPAC to DA ratio. Raclopride (0.2 mg/kg) also partially but significantly reduced the locomotor stimulant effects of d-amphetamine in reserpinized mice. Biochemical analyses in the striata indicated that CY208243 slightly retarded DA turnover (as assessed by the DOPAC/DA ratio). SKF38393 itself also slightly reduced DA turnover. In automated activity cages, using mice depleted of DA with reserpine and alpha-methyltyrosine, all the D-2 receptor agonists tested, in combination with SKF38393, produced an increase in activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Release of 3H-5-hydroxytryptamine by amiflamine and related phenylalkylamines from rat occipital cortex slices.

In the present study amiflamine and other related reversible monoamine oxidase-A (MAO-A) inhibitory phenylalkylamines were examined in vitro for their ability to induce release of 3H-5-hydroxytryptamine (3H-5-HT) from rat occipital cortex slices. The slices were preincubated with 3H-5-HT 0.1 mumol/l in the presence of the irreversible MAO inhibitor pargyline 50 mumol/l and then continuously superfused. The effects were compared with those of the 5-HT releaser p-chloroamphetamine (pCA), the reversible MAO-inhibitor alpha-ethyltryptamine and the 5-HT uptake inhibitor citalopram. Amiflamine, some related compounds and alpha-ethyltryptamine which in vivo after transport by the 5-HT uptake mechanism preferentially inhibit MAO within the serotonergic neurons caused a Ca2+-independent release of 3H-5-HT. Some transported compounds, particularly NBF 027 were, however, very weak releasers of 5-HT. This release and that induced by pCA was prevented by citalopram in the superfusion medium. FLA 365, FLA 417 and FLA 1088, which are not transported into the neurons, were poor releasers of 5-HT. It is concluded that compounds which were effective releasers of 5-HT in vitro were those that are transported into the serotonergic neurons by the 5-HT carrier in vivo and has in addition an ability to mobilise vesicular 5-HT.

Aniline Compounds↗
PubMed1989

Kinetic properties of the accumulation of 3H-raclopride in the mouse brain in vivo.

The kinetic properties of the accumulation of 3H-raclopride, a selective dopamine (DA) D-2 receptor antagonist, in mouse striatum in vivo was examined under various experimental conditions. The accumulation in striatum was saturable in contrast to that in cerebellum, which linearily increased with the dose. The specific binding of 3H-raclopride in the striatum, defined as the difference in the accumulation in striatum and cerebellum 30 min after the injection was completely inhibited by the D-2 receptor antagonists spiperone and (+)-butaclamol [but not (-)-butaclamol] and the DA receptor agonist N-n-propylnorapomorphine. The mean Bmax value of the specific binding was 40.7 +/- 2.8 pmol/g tissue and the mean apparent KD value, based on the dose injected, was 87.8 +/- 11.5 nmol/kg i.v. (18 different experiments). Pretreatment of the mice with a single injection of reserpine 4 h or 3 days beforehand reduced the apparent KD value which in part seemed to be due to the decreased concentration of synaptic DA. Similarly, gamma-butyrolactone injected immediately before raclopride reduced the apparent KD value, whereas amfonelic acid and (-)-amphetamine increased the observed KD values. These findings indicate competition between endogenous DA and raclopride for the D-2 receptors. Both reserpine and gamma-butyrolactone increased the apparent Bmax value by about 50% which indicates a receptor pool of DA for which raclopride does not compete.

4-Butyrolactone↗
PubMed1989

Kinetic properties of the in vivo accumulation of 3H-(-)-N-n-propylnorapomorphine in mouse brain.

(1) The influence of various dopamine (DA) receptor agonists and antagonists on the kinetic properties of the specific binding of 3H(-)-N-n-propylnorapomorphine (NPA) in the mouse striatum in vivo was studied. The specific binding of 3H-NPA, defined as the difference between the radioactivity in the striatum and cerebellum, was completely antagonized by the selective D-2 receptor antagonist raclopride but not by the selective D-1 antagonist SCH 23390, showing that the binding occurs exclusively to the D-2 receptors. (2) The selective D-2 receptor agonists pergolide and quinpirole inhibited the 3H-NPA binding biphasically at low doses, indicating that these DA receptor agonists have high affinities for a subfraction (10 to 30%) of the NPA binding sites. (3) Increasing the synaptic DA concentration by DA release [(+)-amphetamine] or uptake blockade (amfonelic acid and methylphenidate) inhibited the 3H-NPA binding in a competitive manner (unchanged Bmax, increased KD). Depletion of the DA in the synapses by gamma-butyrolactone or reserpine decreased the apparent KD value. (4) The possibility of estimating changes in the synaptic DA concentration from changes in the apparent KD is discussed. According to the results obtained, the normal concentration of DA in the synaptic cleft in mouse striatum in vivo is about 40 nmol/l and this concentration is increased 2 to 3 times by (+)-amphetamine and amfonelic acid in doses which evoke hyperactivity and stereotypic behaviour.

4-Butyrolactone↗
PubMed1989

Dopamine D2 agonist-induced behavioural depression is reversed by dopamine D1 agonists.

The dopamine (DA) D2 agonist bromocriptine produced dose-dependent locomotor depression in mice with intact stores of DA, as measured in automated activity cages. The DA D1 agonist CY208-243, reversed the bromocriptine-induced depression. Using direct observational analysis, another selective DA D2 agonist, quinpirole, induced dose-dependent depression and this was reversed by the D1 agonist SKF38393. The effect of SKF38393 could be blocked by prior pretreatment with SCH23390. It is concluded that DA D2 agonist-induced locomotor depression is mediated via a DA D2 autoreceptor-mediated inhibition of DA release onto postsynaptic DA receptors. This reduction in release probably deprives postsynaptic D1 and D2 receptors of endogenous DA. However, since bromocriptine (and probably quinpirole) in all likelihood occupies both pre- and postsynaptic D2 receptors immediately on injection, and since CY208-243 and SKF38393 (respectively) could reverse the depression, the depression seems to be due specifically to a deprivation of DA at postsynaptic D1 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

[3H]desipramine binding to rat brain tissue: binding to both noradrenaline uptake sites and sites not related to noradrenaline neurons.

The pharmacological and biochemical characteristics of [3H]desipramine binding to rat brain tissue were investigated. Competition studies with noradrenaline, nisoxetine, nortriptyline, and desipramine suggested the presence of more than one [3H]desipramine binding site. Most of the noradrenaline-sensitive binding represented a high-affinity site, and this site appeared to be the same as the high-affinity site of nisoxetine-sensitive binding. The [3H]desipramine binding sites were abolished by protease treatment, a result suggesting that the binding sites are protein in nature. When specific binding was defined by 0.1 microM nisoxetine, the binding was saturable and fitted a single-site binding model with a binding affinity of approximately 1 nM. This binding fraction was abolished by lesioning of the noradrenaline neurons with the noradrenaline neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). In contrast, when 10 microM nisoxetine was used to define the specific binding, the binding was not saturable over the nanomolar range, but the binding fitted a two-site binding model with KD values of 0.5 and greater than 100 nM for the high- and low-affinity components, respectively. The high-affinity site was abolished after DSP4 lesioning, whereas the low-affinity site remained. The binding capacity (Bmax) for binding defined by 0.1 microM nisoxetine varied between brain regions, with very low density in the striatum (Bmax not possible to determine), 60-90 fmol/mg of protein in cortical areas and cerebellum, and 120 fmol/mg of protein in the hypothalamus. The binding capacities of these high-affinity sites correlated significantly with the regional distribution of [3H]noradrenaline uptake but not with 5-[3H]hydroxytryptamine uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Inhibition of monoamine oxidase within monoaminergic neurons in the rat brain by (E)-beta-fluoromethylene-m-tyrosine (MDL 72394).

The irreversible inhibition of the monoamine oxidase (MAO) activity within monoaminergic neurons in the rat brain 24 h after single or repeated administration of (E)-beta-fluoromethylene-m-tyrosine (FMMT, MDL 72394) was examined. The enzyme activity was determined by incubating synaptosome-rich homogenates of hypothalamus or striatum with low concentrations of 5-[14C]hydroxytryptamine (5-HT), [14C]noradrenaline (NA), or [14C]dopamine (DA) in the absence and presence of the selective amine uptake inhibitors citalopram (5-HT), maprotiline (NA), and GBR 12909 (DA). After a single subcutaneous injection of FMMT, the inhibition of MAO within the noradrenergic and dopaminergic neurons was significant but only slightly greater than that outside these neurons. The opposite relationship was observed for the serotonergic neurons. After 7 days' treatment of rats with carbidopa, 20 mg/kg p.o., + FMMT once daily, the preference for the inhibition of MAO within the noradrenergic and dopaminergic neurons was accentuated further. The inhibition outside the serotonergic neurons was still greater than within these neurons. The NA uptake inhibitor CPP 199 antagonized the selective inhibition of MAO within the noradrenergic neurons, which indicates that this preference is due to the accumulation of the active metabolite (E)-beta-fluoromethylene-m-tyramine by the NA transporter.

Animals↗
PubMed1989

The involvement of dopamine D1 and D2 receptors in the locomotor stimulation produced by (+)-amphetamine in naive and dopamine-depleted mice.

The interaction between (+)-amphetamine and dopamine (DA) D1 and D2 receptors was investigated. In naïve mice, i.e., mice with intact stores of DA, both the selective D1 antagonist SCH23390 and the selective D2 antagonist spiperone blocked the locomoter stimulation produced by (+)-amphetamine. The selective D1 agonist SKF38393 (6 mg/kg intraperitoneally) did not produce a consistent dose-dependent effect on the response to (+)-amphetamine in naïve mice. In mice depleted of DA with reserpine 24 hr before a challenge with (+)-amphetamine, neither SCH23390 nor spiperone were completely effective in blocking (+)-amphetamine. A combination of spiperone plus SCH23390 was, however, more effective than either drug alone, although significant activity remained even after the combination. In mice pretreated with reserpine and various doses of alpha methyl-p-tyrosine (alpha MPT, intraperitoneally), the degree of stimulation produced by (+)-amphetamine was dependent on the amount and frequency of alpha MPT dosage - the higher and more frequent the dose, the more effective the blockade. In these animals, both SKF38393 and the selective D2 agonist quinpirole potentiated the stimulation induced by (+)-amphetamine when the dose of alpha MPT was not maximal. However, in those animals pretreated with reserpine plus two doses each of 400 mg/kg alpha MPT, neither SKF38393 nor quinpirole were effective in potentiating (+)-amphetamine. Nevertheless, when SKF38393 and quinpirole were administered simultaneously to these mice, marked locomotor stimulation occurred implying that the pretreatment itself had not rendered the mice incapable of locomotion.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

The motor effects of bromocriptine--a review.

For many years, bromocriptine has proven to be a useful treatment for some of the disabling motor effects seen in Parkinson's disease. As such, it has been the only commonly used directly acting D2 agonist available. But its mechanism of action has been obscure because many animal models indicated an absolute requirement for the presence of endogenous DA for bromocriptine to have any efficacy, despite its undoubted occupation of the D2 receptor with high affinity. Several scattered reports indicated, however, that bromocriptine could potentiate the effects of a number of other dopamine agonists (such as apomorphine and L-dopa) in a variety of pharmacological models and in the clinic. With the availability of SKF38393 and SCH23390, it soon became clear that bromocriptine, while a selective D2 agonist, depended in an absolute sense on the integrity of the D1 receptors. Thus, if SKF38393 was administered together with bromocriptine to rodents depleted of dopamine, marked locomotor excitation was produced, despite either drug alone being inactive. The present review explores the literature on the motor effects of bromocriptine and endeavours to integrate its behavioural, biochemical and electrophysiological effects into a coherent whole. It closes with a consideration of several remaining unsolved problems associated with the pharmacology of bromocriptine and suggests some future studies.

Animals↗
PubMed1988

Further studies on the interaction between bromocriptine and SKF38393 in reserpine and alpha methyl-para-tyrosine-treated mice.

In a previous report, we showed that the relatively selective dopamine (DA) D-2 agonist bromocriptine (BRC), when combined with the selective D-1 agonist SKF38393, produced in DA-depleted mice a marked locomotor stimulation, despite BRC and SKF38393 being inactive by themselves (Jackson and Hashizume 1986). The present series of experiments was designed to further explore this interaction. In all experiments, mice were pretreated with reserpine and/or alpha methyl-p-tyrosine (AMPT). In mice pretreated with reserpine, AMPT or reserpine plus AMPT, BRC plus SKF38393 produced marked excitation whether the BRC was given 3 or 1 h prior to the SKF38393 challenge. However, while there was no absolute requirement that BRC be given a certain time before SKF38393, this factor was of some importance, with the onset of locomotor stimulation produced by the combination being much more rapid if the BRC was given 3 h rather than 1 h before the SKF38393. Interestingly, the degree of locomotor stimulation produced by the combination was always greatest in the animals premedicated with reserpine alone. If AMPT was also used (with or without reserpine), the stimulation produced by the combination was reduced, which may have resulted in part from a non-specific depressant effect of the AMPT. From these results, it seems as though endogenous DA is not required for BRC to work, provided that D-1 receptors are stimulated.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Selective inhibition by 4,alpha-dimethyl-m-tyramine (H77/77) and 4-methyl-alpha-ethyl-m-tyramine (H75/12) of the monoamine oxidase within serotonergic and noradrenergic neurons in the rat brain.

1. The inhibition of monoamine oxidase (MAO) by 4, alpha-dimethyl-m-tyramine (H77/77) and 4-methyl-alpha-ethyl-m-tyramine (H75/12), two amine releasing compounds, within monoaminergic neurons in the rat hypothalamus and striatum in vivo was determined. This was performed by measuring the protection of MAO by the test compound against the irreversible inhibition produced by phenelzine. The MAO activity inside and outside monoaminergic synaptosomes in homogenates of brain tissue was measured in the absence and presence of selective uptake inhibitors at low concentrations of 14C-labelled 5-hydroxytryptamine, noradrenaline or dopamine. 2. It was found that H77/77 and H75/12 produced a pronounced protection against phenelzine within the serotonergic and noradrenergic neurons, whereas much less effect was observed outside these neurons. 3. It was shown that the protection by H75/12 within the serotonergic neurons was somewhat reduced in 5-HT depleted reserpinized rats and that the protection outside these neurons was abolished. Some of the protection of MAO might therefore have been brought about by 5-HT molecules released by H75/12. 4. The marked inhibition of MAO within serotonergic and noradrenergic neurons was counteracted by amine uptake inhibitors and is accordingly brought about by the high concentrations of the accumulated compounds. 5. In contrast to other neuron selective MAO inhibitors, H75/12 decreased the 5-HT concentration in the hypothalamus showing that the releasing effect dominated over the MAO inhibitory effect.

Amphetamines↗
PubMed1988

Unaltered 5-HT- and desipramine-sensitive [3H]imipramine binding and [3H]5-HT uptake in rat brain after chronic imipramine and norzimeldine treatment.

Several reports have shown heterogeneity of [3H]imipramine binding to brain membranes. Recently, a high affinity and 5-HT sensitive [3H]imipramine binding site of protein nature, that was suggested to be identical to the substrate recognition site for 5-HT uptake, was demonstrated. Since most studies on the regulation of the [3H]imipramine binding sites by antidepressants have used desipramine displaceable binding, which is heterogenous in nature and contains binding not related to 5-HT uptake sites, the present report studies the possible effects of chronic (3 weeks) administration of imipramine or norzimeldine (10 mg/kg intraperitoneally twice daily) on 5-HT sensitive [3H]imipramine binding sites. For comparison, desipramine sensitive binding was also studied, as well as the physiological correlate 5-HT uptake. There were no changes in either [3H]imipramine binding or 5-HT uptake after the antidepressant treatment.

Animals↗
PubMed1988

Enhancement by a single dose of reserpine (plus alpha methyl-p-tyrosine) of the central stimulatory effects evoked by dopamine D-1 and D-2 agonists in the mouse.

With the advent of selective dopamine D-1 and D-2 agonists such as SKF38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine HCl) and quinpirole (LY171555, trans-4,4a,5,6,7,8a,9-octahydro-5-propyl-2H-pyrazolo [3,4-g]quinoline), it has become possible to examine the functional role of the two dopamine receptor subtypes as well as their interrelationship. In the present study, we pretreated mice with the granule-depleting agent reserpine (5 mg/kg sc) and tested the mice from 4 h to 10 days later. In all the studies, each mouse also received an injection of the dopamine synthesis inhibitor alpha methyl-p-tyrosine (200 mg/kg ip) 1 h before agonist challenge. Where the reserpine was given 2 or more days before testing, a second dose of reserpine was given 4 h before agonist challenge. While producing no significant locomotor stimulation 4 h after reserpine, SKF38393 produced a dose-dependent increase in coordinated locomotion 24 h and 3 days after the reserpine. Likewise, quinpirole itself produced no significant alteration in activity at 4 h, but significantly increased activity at 24 h and 3 days. The new selective D-1 agonist CY208-243 ((-)-4,6,6a,7,8,12b-hexahydro-7-methyl-indolo [4,3-ab] phenanthridine), unlike SKF38393, produced some increase in activity 4 h after reserpine, but much greater activity was seen 1 and 3 days after reserpine. The enhancement with SKF38393, CY208-243 and quinpirole was most marked 3 days after the reserpine. The behavioural stimulation produced by the mixed D1/D2 agonist apomorphine was also greater 3 days after reserpine pretreatment than after 4 h.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Homoallylic amines related to zimeldine. A comparative study on neuronal serotonin and norepinephrine reuptake based on conformational analysis.

A number of tertiary and secondary homoallylic amines, i.e. (Z)- and (E)-4-(4-bromophenyl)-4-(3-pyridyl)-3-buten-1-ylamines, were synthesized in diastereomerically pure forms. The compounds were evaluated as neuronal norepinephrine (NE) and serotonin (5-HT) uptake inhibitors under in vitro and ex vivo conditions and compared with the tricyclics amitriptyline and nortriptyline having homoallylic side chains and with the corresponding diastereomers in the zimeldine series having allylic side chains. The Z isomers of the new homoallylic derivatives (3Z, 4Z) were specific 5-HT uptake inhibitors in analogy with the corresponding allylic derivatives zimeldine (1Z) and norzimeldine (2Z). Likewise, the selectivity profile of the homoallylic (3E, 4E) and the allylic (1E, 2E) derivatives was comparable. In general, the homoallylic compounds were less potent inhibitors than their allylic counterparts. The similarities and discrepancies were evaluated in terms of conformational preferences determined by CAMSEQ molecular mechanics calculations. Homonorzimeldine (4Z) can accommodate energetically favored, but less populated, conformations having amino nitrogen atom to aromatic ring center distances comparable to those in norzimeldine. These facts correlate to retained 5-HT selectivity but diminished potency of 4Z compared to 2Z.

Animals↗