Jens-Jørgen Larsen

Pharmacological effects of a specific dopamine D-1 antagonist SCH 23390 in comparison with neuroleptics

Neuroleptics such as thioxanthenes (cis(Z)-flupentixol and cis(Z)-clopenthixol) and phenothiazines (fluphenazine and perphenazine), which block both dopamine (DA) D-1 and D-2 receptors and the butyrophenones (haloperidol and spiroperidol), which block D-2 receptors only, are equipotent both behaviorally and clinically. A new compound SCH 23390 which selectively blocks DA D-1 receptors, resembles many neuroleptics in its pharmacological profile: antistereotypic effects in mice, rats and dogs, cataleptogenic effect and inhibitory effect on amphetamine circling. In contrast SCH 23390 has no effect on apomorphine-induced vomiting in dogs and little effects on 6-OHDA-denervated supersensitive DA receptors, stimulated by the DA agonist 3-PPP. In a series of experiments where methylphenidate-induced stereotyped gnawing in mice was inhibited by neuroleptics, it was shown that concomitant treatment with scopolamine or diazepam attenuated the effect of butyrophenones (D-2 antagonists). The same treatment attenuated the effect of phenothiazines, to a lesser extent, and hardly attenuated the effect of thioxanthenes and SCH 23390 at all. It is concluded that DA D-1 receptors are as important as D-2 receptors for the expression of neuroleptic activity in most animal models believed to be predictive of antipsychotic and extrapyramidal side-effect potential. However, the D-1 antagonist is less sensitive than D-2 antagonists to antimuscarinic compounds and benzodiazepines.

Neurochemical profile of Lu 19-005, a potent inhibitor of uptake of dopamine, noradrenaline, and serotonin

Abstract: The neurochemical profile of a new compound, Lu 19–005 [(±)trans‐3‐(3,4‐dichlorophenyl)‐N‐methyl‐1‐indanamine hydrochloride], has been investigated. Lu 19–005 is a potent inhibitor of the synaptosomal uptake of 3,4‐dihydroxyphenylethylamine (dopamine, DA), noradrenaline (NA), and 5‐hydroxytryptamine (5‐HT, serotonin). In this respect it resembles diclofensine, whereas compounds such as GBR 13.069 and bupropion are more selective DA‐uptake inhibitors. Although Lu 19–005 releases DA in in higher concentrations it must be considered as an uptake inhibitor, as the accumulation of DA is inhibited in much lower concentrations. Lu 19–005 attenuates the DA and NA depletion caused by 6‐hydroxydopamine in mouse brain. These properties confirm the DA‐ and NA‐uptake‐inhibitory properties of the compound. In receptor‐binding models and functional in vitro tests Lu 19–005 is devoid of dopaminergic‐, serotonergic‐, noradrenergic‐, histaminergic‐, and cholinergic‐inhibiting properties. Since DA, NA, and 5‐HT seem to be involved in depression, the profile of Lu 19‐005–with equally potent activity on the three neuronal systems–makes it an interesting experimental tool and a potential new antidepressant agent.

Dopamine receptor agonistic and antagonistic effects of 3-PPP enantiomers

The pharmacological profile of the enantiomers of the proposed selective dopamine (DA) autoreceptor agonist 3-PPP [3-(3-hydroxyphenyl)-N-n-propylpiperidine] has been studied. In vitro both enantiomers showed weak DA agonistic activity, and (-)-3-PPP some DA antagonistic effect on DA-stimulated adenylate cyclase activity. Both enantiomers in low doses had a similar profile in vivo: Inhibition of locomotor activity of mice and rats, induction of contralateral circling behaviour in 6-hydroxy-DA-lesioned rats and an emetic effect in dogs. At higher doses, differential effects of the enantiomers were found: (+)-3-PPP induced hyperactivity, weak stereotyped behaviour and ipsilateral circling in hemitransected rats. (-)-3-PPP had depressant effects in high doses, inhibited d-amphetamine-induced hyperactivity and d-amphetamine-, methylphenidate- and apomorphine-induced stereotyped licking/biting in rats and antagonized apomorphine-induced emesis in dogs. However, (+)-3-PPP also showed a weak antagonistic activity against d-amphetamine-induced hyperactivity and d-amphetamine-and apomorphine-induced stereotypy in rats and inhibited apomorphine-induced emesis in dogs.It is suggested that both enantiomers have significant effects on postsynaptic DA receptors in high doses: (-)-3-PPP with weak antagonistic activity in some test models and (+)-3-PPP with agonistic and antagonistic effect. Since these effects of (+)-3-PPP were of low intensity at high doses, (+)-3-PPP may be a partial DA agonist at postsynaptic receptors in high doses. Interaction experiments with neuroleptics indicated that only (-)-3-PPP significantly increased the antistereotypic effect of neuroleptics in rats. Therefore, the proposed DA autoreceptor stimulation is possibly unrelated to the neuroleptic potentiation.

Effects of putative dopamine autoreceptor agonists in pharmacological models related to dopaminergic and neuroleptic activity.

Abstract The pharmacological profile of 2 proposed selective dopamine (DA) autoreceptor agonists 3-PPP and 3-phenethyl-PP was compared with that of apomorphine in test systems for detection of dopaminergic and antidopaminergic activity. In vitro 3-PPP and 3-phenethyl-PP showed preferential affinity for D-2 DA receptors and only very low affinity for D-1 DA receptors. Accordingly, and in contrast to apomorphine, no stimulation of DA-sensitive adenylate cyclase was observed. A weak to moderate inhibitory activity of all 3 compounds was shown in uptake systems for DA, NA and 5-HT. A weak or no effect on α 1 -or α 2 -adrenergic receptors was observed. 3-PPP, 3-phenethyl-PP and apomorphine inhibited spontaneous locomotor activity in mice and rats, induced contralateral circling behaviour in 6-hydroxy-DA-lesioned rats and induced emesis in dogs. The DA involvement in these effects was confirmed by antagonistic effects of neuroleptics in all three test systems. Apomorphine was the only compound inducing stereotyped behaviour in normal rats and neuroleptically induced supersensitive mice and inducing ipsilateral circling behaviour in hemitransected rats. 3-PPP did not show activity in several tests for neuroleptic effects in vivo, including inhibition of apomorphine- and methylphenidate-induced stereotyped gnawing, cataleptogenic effect, inhibition of conditioned avoidance response and inhibition of 6,7-ADTN-induced hyperactivity after injection into the nucleus accumbens. In contrast 3-PPP and 3-phenethyl-PP antagonized d-amphetamine-induced stereotyped licking/gnawing and hyperactivity. 3-PPP did not influence the cateleptogenic or methylphenidate antagonistic effect of cis-(Z)-flupentixol or haloperidol. 3-PPP increased the methylphenidate antagonistic effect of spiroperidol and the apomorphine antagonistic effect of cis-(Z)-flupentixol, cis-(Z)-clopenthixol and spiroperidol. It is concluded that 3-PPP and its more potent derivative 3-phenethyl-PP show high selectivity for DA receptors mediating sedation in rodents but that these compounds activate DA receptors mediating emesis and activate denervation supersensitive DA receptors, while not affecting neuroleptic supersensitive DA receptors. The neuroleptic-like activity of 3-PPP and 3-phenethyl-PP is only shown as a d-amphetamine antagonistic effect, indicating a presynaptic site of action. The increase of some neuroleptic effects may have clinical relevance for treatment of diseases associated with DA hyperactivity.

SCH 23390 - a selective dopamine D-1 receptor antagonist with putative 5-HT1 receptor agonistic activity

The selective dopamine D-1 receptor antagonist SCH 23390 has been tested in vitro in the rat fundus model and in vivo in the electrically stimulated flexor reflex model. In the fundus model, SCH 23390 showed a potent agonistic activity compared to that of different 5-HT receptor agonists. Pindolol, 1-propranolol and pirenperone showed no or only weak inhibition of the SCH 23390-induced contractions in the fundus strip whereas methysergide was a potent inhibitor. The 5-HT3 receptor antagonist ICS 205-930 did not induce an inhibitory effect. In the electrically stimulated flexor reflex model in pithed rats, SCH 23390 induced a marked increase of the reflex. This increase was slightly inhibited by a mixed dopamine (DA) D-1/D-2 antagonist cis(Z)-flupentixol and by a specific DA D-2 antagonist YM 09151-2. Different reference antagonists: bicuculline (GABAergic), propranolol (beta-adrenergic), scopolamine (muscarinic), yohimbine (alpha 2-adrenergic), prazosin (alpha 1-adrenergic) were all without an antagonist effect on the SCH 23390-induced increase of the flexor reflex. Ketanserin, a selective 5-HT2 receptor antagonist, showed a weak and short-lasting inhibition of the SCH 23390 effect in high doses, whereas ritanserin showed only 35% inhibition of the SCH 23390-induced flexor reflex at a dose of 1.3 mumol/kg i.v. The mixed 5-HT1/5-HT2 antagonists methiothepin and metergoline showed a marked inhibitory effect at 2.6 mumol/kg i.v. and 3.1 mumol/kg i.v., respectively (1.3 mg/kg i.v.). These findings suggest that SCH 23390 might possess 5-HT1 receptor agonist activity.

Influence of pregnancy and sex steroids on concentration, motor effect and receptor binding of VIP in the rabbit female genital tract

The influence of sex steroid and pregnancy on the tissue concentration, uterine motor effect and receptor binding of VIP has been studied in the female genital tract of pregnant rabbits and oophorectomized rabbits during progesterone and/or oestrogen substitution. 1. (1) The concentration of immunoreactive VIP was high in the vagina and cervix, and lower in the uterine body of both pregnant and non-pregnant rabbits. A significant decrease in the VIP concentration (pmol/g wet weight) of the uterine body was observed toward term of pregnancy. The total uterine content of VIP, however, seems unchanged. Treatment of oophorectomized rabbits with ovarian steroids had no effect on the VIP concentration. 2. (2) The sensitivity for and potency of VIP on the relaxation of uterine muscle was significantly higher in oophorectomized rabbits treated with a combination of progesterone and oestrogen than in control rabbits. No difference was observed between non-pregnant and pregnant rabbits. 3. (3) The degradation and binding affinity for 125I-labelled VIP was highest in oophorectomized rabbits substituted with both oestrogen and progesterone. In the pregnant rabbits, the amount of receptors was decreased near term. In conclusion, sex steroids are able to influence the motor effect of VIP at the receptor level, but have no effect on the VIP concentration in the female genital tract.

Subarachnoidal administration of the 5-HT uptake inhibitor citalopram points to the spinal role of 5-HT in morphine antinociception.

Abstract The role of 5‐hydroxytryptamine (5‐HT) in morphine‐induced antinociception was evaluated in mice and rats by means of the specific 5‐HT uptake inhibitor citalopram. Systemic and subarachnoidal administration of the compounds was made and then the animals were tested in the grid‐shock and hot plate model. In non‐antinociceptive doses, systemically and subarachnoidally administered citalopram potentiated the effect of morphine given systemically. In contrast no potentiation was obtained with any of the two routes of administration of citalopram when morphine was injected subarachnoidally. The results support the suggested importance of 5‐HT terminals in mediation of the supraspinal but not the spinal contribution to morphine antinociception.

Pharmacological profile of a novel class of muscarinic acetylcholine receptor agonists

Some in vivo pharmacological effects of a number of muscarinic acetylcholine receptor agonists containing the bicyclic 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THPO) skeleton were studied in rats and mice. The key compounds O,N-dimethyl-THPO (2) and O-methyl-THPO (4) are bioisosteres of arecoline and norarecoline, respectively. The vasodepressor effects of arecoline and the title compounds in anaesthetized rats gave parallel log dose-response curves. The order of potency of the compounds in this test system was identical with that measured earlier using a guinea-pig ileum preparation, arecoline and 2 being the most active compounds. This order of potency was different from those for the antinociceptive and anticonvulsant effects of the compounds using grid shock and isoniazid antagonism tests, respectively, where O-propargyl-THPO (3) proved to be the most active. The pA2 values for the atropine or scopolamine antagonism of these effects of arecoline and 4 were calculated. The partition coefficients (log P values) of the compounds were measured and shown to conform with their ability to penetrate the blood-brain barrier.

Neurotransmitter-role of VIP in non-adrenergic relaxation of feline myometrium

The feline myometrium is heavily innervated by VIP-containing nerve fibres. Transmural electrical stimulation (10 Hz, 2 msec, 150 mA) of muscle strips from feline myometrium in the presence of adrenoreceptor blocking agents caused a muscle relaxation. The smooth muscle relaxation was accompanied by a significant increase in immunoreactive VIP in the superfusate. Both the VIP release and the relaxation were completely annulled by tetrodotoxin, a selective blocker of axonal conduction. Furthermore, passive immunoneutralization with antiserum against VIP markedly reduced the smooth muscle relaxation induced by electrical stimulation. In the light of the previously demonstrated smooth muscle relaxant effect of VIP, the present findings indicate that the peptides may participate as neurotransmitter in non-adrenergic relaxation of the feline myometrium.

Effects of S (+)-3-phenethyl-PP, a putative dopamine autoreceptor agonist with greater autoreceptor selectivity than 3-PPP enantiomers

The experiments concerned the pharmacology of the enantiomers of the phenethyl-analogue (3-phenethyl-PP) of the putative dopamine (DA) autoreceptor agonist 3-PPP. In contrast to the almost equipotency of 3-PPP enantiomers, the phenethyl enantiomers showed marked stereoselectivity. S(+)-3-Phenethyl-PP had 25 times higher affinity to D-2 DA receptors in vitro than the R(-)-enantiomer. In vivo a similar potency difference was seen for the inhibition of motility, induction of circling behaviour in 6-OHDA-lesioned rats and emetic effect in dogs. None of the enantiomers induced stereotypy and hypermotility in normal rats or in rats pretreated with reserpine and alpha-methyl-p-tyrosine. In test models for antidopaminergic activity only slight activity of either enantiomer was observed. The S(+)-enantiomer had no antagonistic effect against apomorphine- and amphetamine-induced stereotypies, no cataleptogenic activity and only partially antagonized amphetamine-induced hypermotility. Apomorphine-induced emesis was weakly antagonized. The results indicate a greater and higher selectivity of S(+)-3-phenethyl-PP for DA receptors mediating sedation compared with 3-PPP enantiomers which previously have been shown to exert significant effects on postsynaptic DA receptors. Thus S(+)-3-phenethyl-PP may be a more selective model compound for the differential study of effects elicited by stimulation of pre- and postsynaptic DA receptors.