3-PPP, a new centrally acting DA-receptor agonist with selectivity for autoreceptors

Stephan, Holger; Carlsson, Arvid; Wikström, Håkan; Lindberg, Per; Sánchez, Domènec J.; Hacksell, Uli; Arvidsson, L.-E.; Svensson, U; Nilsson, Jonas

doi:10.1016/0024-3205(81)90448-3

Cited by 232 publications

(44 citation statements)

References 17 publications

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“…The selective labeling of the pars compacta in the guinea pig contrasted with the low to moderate density of labeling present throughout the substantia nigra of the rat. In addition, very dense binding (27)(28)(29), has been shown to be selective for oa sites in rat brain membrane binding assays (21). In the present study, we have confirmed these findings in the guinea (14,15,19,20 (12) have argued that the behavioral effects of both PCP and psychotomimetic benzomorphan opiates are mediated by the haloperidol-insensitive PCP site to which benzomorphan opiates bind with moderate affinity (20,26).…”

supporting

confidence: 80%

1,3-Di(2-[5-3H]tolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs.

Weber¹,

Sonders²,

Quarum³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

286

144

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supporting

confidence: 80%

1,3-Di(2-[5-3H]tolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs.

Weber¹,

Sonders²,

Quarum³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

286

144

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“…An unexpected finding in the present study was the inhibitory action on neurogenic twitches of low concentrations of (+ )-3-PPP via dopamine D2-receptors, even though (+ )-3-PPP was originally studied as a D2-agonist (Hjorth et al, 1981). Firstly, such an action was not reported by Campbell et al (1987).…”

Section: Discussioncontrasting

confidence: 37%

An examination of the putative σ‐receptor in the mouse isolated vas deferens

Kennedy

Henderson

1989

British J Pharmacology

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The effects of several ligands which interact with the σ‐binding site were studied on the electrically‐evoked (0.1 Hz) neurogenic twitch contractions of the mouse isolated vas deferens. (+)‐3‐(3‐Hydroxyphenyl)‐N‐(1‐propyl)piperidine ((+)‐3‐PPP) (10−8–10−5m), inhibited the neurogenic twitch contractions. This inhibitory action was unaffected by naloxone (10−6m), idazoxan (10−6m), cocaine (10−6m) or tyramine (10−4–3 × 10−4m), but was abolished by the dopamine D2‐antagonist, sulpiride (10−6m). Therefore, in order to study the potentiating actions of σ ligands, sulpiride (10−6m) was used to prevent any inhibitory actions mediated via dopamine D2‐receptors. In the presence of sulpiride (10−6m), haloperidol (10−6–10−5m), (+)‐3‐PPP (10−6−3 × 10−4m) and (+)‐N‐allyl‐N‐normetazocine ((+)‐SKF 10,047) (10−5–10−4m) each reversibly potentiated the neurogenic twitch contractions in a concentration‐dependent manner. The rank order of potency was haloperidol > (+)‐3‐PPP > (+)‐SKF 10,047. The stereoisomers of 3‐PPP displayed stereoselectivity with (+)‐3‐PPP being more potent than (−)‐3‐PPP. At a concentration that did not potentiate the twitch contractions, (3 × 10−7m), haloperidol did not antagonize the potentiating action of (+)‐3‐PPP (3 × 10−5m). 1,3‐Di‐O‐tolyguanidine (DTG) (10−8–10−5m) had no effect on the amplitude of twitch contractions and did not affect the potentiating action of (+)‐3‐PPP (10−5−3 × 10−5m). It is concluded that σ‐ligands potentiate neurogenic twitch contractions of the mouse isolated vas deferens via a site that is different from the central σ‐binding site.

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“…Agonist effect on dopamine autoreceptor was evaluated by measuring inhibitory effect on DOPA accumulation after treatment with reserpine and 3-hydroxybenzylhydrazine dihydrochloride (NSD-1015, a DOPA decarboxylase inhibitor) (Hjorth et al, 1981;Yasuda et al, 1988). Reserpine (1 mg/kg s.c.) was injected, after which rats were fasted for 18 hours before death.…”

Section: Reserpine-induced Dopa Accumulation Assay In Rat Striatummentioning

confidence: 99%

Brexpiprazole I: In Vitro and In Vivo Characterization of a Novel Serotonin-Dopamine Activity Modulator

Maeda

Sugino

Akazawa

et al. 2014

J Pharmacol Exp Ther

284

299

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Brexpiprazole piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity (K i , 1 nM) to human serotonin 1A (h5-HT 1A )-, h5-HT 2A -, long form of human D 2 (hD 2L )-, ha 1B -, and ha 2C -adrenergic receptors. It displayed partial agonism at h5-HT 1A and hD 2 receptors in cloned receptor systems and potent antagonism of h5-HT 2A receptors and ha 1B/2C -adrenoceptors. Brexpiprazole also had affinity (K i , 5 nM) for hD 3 -, h5-HT 2B -, h5-HT 7 -, ha 1A -, and ha 1D -adrenergic receptors, moderate affinity for hH 1 (K i 5 19 nM), and low affinity for hM 1 receptors (K i . 1000 nM). Brexpiprazole potently bound to rat 5-HT 2A and D 2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT 1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT 2A antagonism. Furthermore, in vivo D 2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D 2 partial agonist activity. In particular, based on a lower intrinsic activity at D 2 receptors and higher binding affinities for 5-HT 1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D 2 receptor agonistand antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders.

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3-PPP, a new centrally acting DA-receptor agonist with selectivity for autoreceptors

Cited by 232 publications

References 17 publications

1,3-Di(2-[5-3H]tolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs.

1,3-Di(2-[5-3H]tolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs.

An examination of the putative σ‐receptor in the mouse isolated vas deferens

Brexpiprazole I: In Vitro and In Vivo Characterization of a Novel Serotonin-Dopamine Activity Modulator

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