Tetrahydroisoquinolines as dopaminergic ligands: 1Butyl7-chloro-6-hydroxy-tetrahydroisoquinoline, a new compound with antidepressant-like activity in mice (original) (raw)
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European Journal of Pharmacology, 2014
Forced swimming test Chronic mild stress Models of depression Imipramine Metabolism of monoamines Rat brain a b s t r a c t 1,2,3,4-Tetrahydroisoquinoline (TIQ) is an exo-and endogenous amine naturally present in mammalian brain which displays antidepressant-like effect in various animal models: the forced swim test (FST) and chronic mild stress (CMS) paradigm in rats. To elucidate this action we compared the effects of TIQ with imipramine, a classic antidepressant drug and one of the most clinically effective. Applied behavioral tests showed that TIQ produced an antidepressant-like effect with a potency comparable to that of imipramine. TIQ (25-50 mg/kg i.p.), similarly to imipramine (10-30 mg/kg i.p.), reduced the immobility time in FST and completely reversed the decrease in sucrose intake caused by CMS in the rat. In addition, in order to avoid the possible psychostimulating effect of TIQ we examined the influence of its administration on locomotor activity in rats. TIQ, like imipramine, produced a reduction in horizontal locomotor activity. This suggested that TIQ did not have psychostimulant properties and that prolonged swimming in the FST was a result of an increased motivation to escape from the stressful situation. The biochemical analyses have shown that TIQ activates monoaminergic systems as a reversible monoamine oxidase (MAO) inhibitor and free radical scavenger. Beyond the activation of noradrenaline and serotonin systems, TIQ also moderately affects the dopamine system. On the basis of the presented behavioral and biochemical studies we suggest that TIQ is a potential new antidepressant which may be effective for the depression therapy in a clinical setting.
ChemInform, 1996
The present work reports the synthesis and preliminary pharmacological characterization of 8,9-dihydroxy-2,3,7,11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline (4, dinapsoline). This molecule was designed to conserve the essential elements contained in our D 1 agonist pharmacophore model (i.e., position and orientation of the nitrogen, hydroxyls, and phenyl rings). It involved taking the backbone of dihydrexidine [3; (()-trans-10, 11-dihydroxy-5,6,6a,7,8,12bhexahydrobenzo[a]phenanthridine], the first high-affinity full D 1 agonist, and tethering the two phenyl rings of dihydrexidine through a methylene bridge and removing the C(7)-C(8) ethano bridge. Preliminary molecular modeling studies demonstrated that these modifications conserved the essential elements of the hypothesized pharmacopore. Dinapsoline 4 had almost identical affinity (K I ) 5.9 nM) to 3 at rat striatal D 1 receptors and had a shallow competition curve (n H ) 0.66) that suggested agonist properties. Consistent with this, in both rat striatum and C-6-mD 1 cells, dinapsoline 4 was a full agonist with an EC 50 of ca. 30 nM in stimulating synthesis of cAMP via D 1 receptors. The design and synthesis of dinapsoline 4 provide a powerful test of the model of the D 1 pharmacophore we have developed and provide another chemical series that can be useful probes for the study of D 1 receptors. An interesting property of 3 is that it also has relatively high D 2 affinity (K 0.5 ) 50 nM) despite having an accessory phenyl ring usually thought to convey D 1 selectivity. Dinapsoline 4 was found to have even higher affinity for the D 2 receptor (K 0.5 ) 31 nM) than 3. Because of the high affinity of 4 for D 2 receptors, it and its analogs can be powerful tools for exploring the mechanisms of "functional selectivity" (i.e., that 3 is an agonist at some D 2 receptors, but an antagonist at others).
Neuropsychopharmacology, 2005
Dopamine plays a role in the pathophysiology of depression and therapeutic effects of antidepressants but the contribution of individual D 2 -like receptor subtypes (D 2 , D 3 , D 4 ) to depression is not known. We present evidence that activation of D 2 /D 3 , but not D 4 receptors, can affect the outcome in the rat forced swim test (FST). Nomifensine, a dopamine uptake inhibitor (7, 14, and 28 mmol/kg); quinpirole, a D 2 -like receptor and agonist (0.4, 1.0, and 2.0 mmol/kg); PD 12,8907, a preferential D 3 receptor agonist (0.17, 0.35, and 0.7 mmol/kg); PD 168077 (0.1, 0.3, and 1.0 mmol/kg) and CP 226269 (0.3, 1.0, and 3.0 mmol/kg), both selective D 4 receptor agonists, were administered s.c. 24, 5, and 0.5/1 h before testing. Nomifensine, quinpirole at all doses and PD 128907 at the highest dose decreased immobility time in FST. PD 168077 and CP 226269 had no effect on the model. To further clarify what type of dopamine receptors were involved in the anti-immobility effect of quinpirole, we tested different antagonists. Haloperidol, a D 2 -like receptor antagonist (0.27 mmol/kg), completely blocked the effect of quinpirole; A-437203 (LU-201640), a selective D 3 receptor antagonist (17.46 mmol/kg), showed a nonsignificant trend to attenuate the effect of the low dose of quinpirole, and L-745,870, a selective D 4 receptor antagonist (1.15 mmol/kg), had no effect. The pharmacological selectivity of the compounds tested suggests that the antidepressant-like effects of quinpirole are most likely mediated mainly by D 2 and to a lesser extent by D 3 but not D 4 receptors.
Molecular Pharmacology, 2010
In view of the therapeutic importance of dopamine D 3 and D 2 receptors, there remains considerable interest in novel ligands. Herein, we show that the tetrahydroisoquinoline 1H-indole-2carboxylic acid {4-[2-(cyano-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-cyclohexyl}-amide (SB269,652) behaves as an atypical, allosteric antagonist at D 3 and D 2 receptors. Accordingly, SB269,652 potently (low nanomolar range) abolished specific binding of [ 3 H]nemanopride and [ 3 H]spiperone to Chinese hamster ovary-transfected D 3 receptors when radioligands were used at 0.2 and 0.5 nM, respectively. However, even at high concentrations (5 M), SB269,652 only submaximally inhibited the specific binding of these radioligands when they were employed at 10-fold higher concentrations. By analogy, although SB269,652 potently blocked D 3 receptor-mediated activation of G␣ i3 and phosphorylation of extracellular-signal-regulated kinase (ERK)1/2, when concentrations of dopamine were increased by 10-fold, from 1 M to 10 M, SB269,652 only submaximally inhibited dopamine-induced stimulation of G␣ i3. SB269,652 (up to 10 M) only weakly and partially (by approximately 20-30%) inhibited radioligand binding to D 2 receptors. Likewise, SB269,652 only submaximally suppressed D 2 receptor-mediated stimulation of G␣ i3 and G␣ qi5 (detected with the aequorin assay) and phosphorylation of ERK1/2 and Akt. Furthermore, SB269,652 only partially (35%) inhibited the dopamine-induced recruitment of -arrestin2 to D 2 receptors. Finally, Schild analysis using G␣ i3 assays, and studies of radioligand association and dissociation kinetics, supported allosteric actions of SB269,652 at D 3 and D 2 receptors.
Indian Journal of Pharmacology, 2013
Objective: The present study was designed to investigate the antidepressant potential of N-n-butyl-3-ethoxyquinoxalin-2-carboxamide (6p), a novel 5-HT 3 receptor antagonist in rodent behavioral models of depression. Materials and Methods: The compound 6p was examined in various behavioral models like forced swim test (FST), tail suspension test (TST), mechanistic models [5-hydroxytryptophan (5-HTP)-induced head twitch and reserpine-induced hypothermia (RIH)], and in chronic surgery model-olfactory bulbectomy in rats. Results: Compound 6p (1, 2, and 4 mg/kg, i.p.) exhibited antidepressant-like effect in FST and TST after acute treatment without having an effect on baseline locomotor activity. Moreover, 6p (2 mg/kg, i.p.), potentiated the 5-HTP-induced head twitch responses in mice and inhibited the RIH in rats. Chronic treatment (14 days) with 6p (1 and 2 mg/kg, p.o.) and paroxetine (10 mg/kg, p.o.) in rats significantly reversed the behavioral anomalies induced by bilateral olfactory bulbectomy using open field exploration. Conclusion: The preliminary studies reveal that compound 6p exhibits antidepressant-like effect in behavioral rodent models of depression.
ChemBioChem, 2004
Based on N-alkylated 1,2,3,4-tetrahydroisoquinoline derivatives, which are structurally related to the partial agonist BP 897, a series of novel, selective dopamine D 3 receptor antagonists has been synthesised. Derivatisation included changes in the arylamide moiety and the tetrahydroisoquinoline substructure leading to compounds with markedly improved selectivities and affinities in the low nanomolar concentration range. From the 55 structures presented here, (E)-3-(4-iodophenyl)-N-(4-(1,2,3,4-tetrahydroisoquinolin-2-yl)butyl)acrylamide (51) has high affinity (K i (hD 3 ) 12 nM) and a 123-fold preference for the D 3 receptor relative to the D 2 receptor subtype. Its pharmacological profile offers the prospect of a novel radioligand as a tool for various dopamine D 3 -receptorrelated in vitro and in vivo investigations.
European Journal of Pharmacology, 1987
8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective serotonin1A receptor agonist, was studied for its anti-immobility activity in the forced swimming test after different schedules of treatment. Single doses of 0.250 and 0.500 mg/kg 8-OH-DPAT s.c. reduced the immobility time of rats with no effect on open-field activity. Similar results were obtained with a three-injection course of 8-OH-DPAT in 24 h (doses from 0.125 to 0.500 mg/kg s.c.) or with a once daily injection of 0.250 mg/kg s.c. 8-OH-DPAT for 7 or 21 days. Methiothepin 0.2 mg/kg s.c. and 1-propranolol 20 mg/kg s.c. significantly antagonized the anti-immobility effect of three injections of 0.25 mg/kg s.c. 8-OH-DPAT but 2 mg/kg i.p. metergoline had no such effect. The effect of 8-OH-DPAT was also antagonized both by 0.5 mg/kg i.p. haloperidol and 100 mg/kg i.p. sulpiride, and in animals given an intracerebroventricular injection of 150 micrograms 5,7-dihydroxytryptamine to deplete brain serotonin levels. The results show that 8-OH-DPAT, by acting on serotonin neurons in the brain, produces disinhibitory effects in a rat model predictive of antidepressant activity and suggest that serotonin1A agonists such as 8-OH-DPAT could constitute a novel class of rapid-acting antidepressant agents.
Bioorganic & Medicinal Chemistry, 2012
Two series of arylpiperazinyl-alkyl quinoline-, isoquinoline-, naphthalene-sulfonamides with flexible (13-26) and semi-rigid (33-36) alkylene spacer were synthesized and evaluated for 5-HT 1A , 5-HT 2A , 5-HT 6 , 5-HT 7 and selected compounds for D 2 , D 3 , D 4 receptors. The compounds with a mixed 5-HT and D receptors profile 16 (N-{4-[4-(3-chlorophenyl)-piperazin-1-yl]-butyl}-3-quinolinesulfonamide) and 36 (4-(4-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethyl}-piperidine-1-sulfonyl)-isoquinoline), displaying antagonistic activity at 5-HT 7 , 5-HT 2A , D 2 postsynaptic sites, produced antidepressant-like effects in the forced swim test in mice and showed significant anxiolytic activity in the plus-maze test in rats. The lead compound 36, a multi-receptor 5-HT 2A /5-HT 7 /D 2 /D 3 /D 4 agent, also displayed significant antipsychotic properties in the MK-801-induced hyperlocomotor activity in mice.
—This study investigated the antidepressant-like effect of 4-amine derivatives of 10,11-dihydro-5H-dibenzo-alkylamine-cycloheptane, 4-amine (3-N,N-dimethylpropylamine)-10,11-dihydro-5H-dibenzo[a,d]cycloheptane-5-one (ADDCH1) and 1,2,3,4,8,9-hexahydro-dibenzocyclohepta[4,4a,5-ef]1,4-diazepin (ADDCH2), in a validated experimental model of depression, the forced swimming test (FST) in mice. Female adult mice were sub-chronically (three doses in 24 h) or repeatedly (once a day for 10 days) treated with either of the compounds and evaluated in the FST. The sub-chronic treatment promoted a dose-dependent reduction in the immobility time in the FST with the doses of 50 mg/kg (ADDCH1) and 30 mg/kg (ADDCH2) ip being the most effective (33% and 37% of reduction, respectively). A similar profile of action was observed in the animals repeatedly treated with ADDCH1 50 mg/kg or ADDCH2 30 mg/kg ip (for 10 days) and there was no sign of motor impairment or locomotor activation as evaluated in the rota-rod and open-field tests, respectively. These findings suggest that these amine derivatives of the system dibenzo-cycloheptane have an antidepressant-like action which could be of clinical interest and, therefore, deserves further investigation. In addition, putative underlying mechanisms of action are discussed.