D2 dopamine receptor (Ki = 2.4, 100 and 220 nM for D2, D3 and D4 receptors)

The D3/D2 and D4/D2 selectivity ratios are 15 times and 136 times, respectively, according to intrinsic activity in functional assays that use the inhibition of quinpirole-stimulated mitosis of human dopamine D2 or D3 receptors transfected into Chinese Hamster Ovary (CHO) cells, L-741626, prepared by literature methods (Ki (D2) = 11.2 nM). L-741626 is a strong antagonist in functional experiments (EC50 (D2)=4.46 nM) with a moderate degree of D2 selectivity (EC50 (D3)=90.4 nM) [2].

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The parent molecule L741,626 was prepared by literature methods10 (Ki (D2) = 11.2 nM) and displayed a D3/D2 and D4/D2 selectivity ratio of 15-fold and 136-fold, respectively. In the functional assay L-741626 was a potent antagonist (EC50 (D2) = 4.46 nM) with some D2 selectivity (EC50 (D3) = 90.4 nM).[2]
L-741626 exhibited a complete reversal of the previously observed selectivity, now having 100-fold selectivity for the D2 receptor. [4]

In male Sprague Dawley rats trained on pramipexole, L-741626 (1.0 mg/kg; ih) successfully moves the pramipexole dose-response curve to the right [3]. Adult mice's increased production of TNF-α in microglia was decreased when cocaine and the D2 antagonist L-741626 (3 mg/kg; i.p.; 15 min before cocaine) were given together for 5 days [4].

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Co-administrating cocaine with the D2 antagonist L-741626 for 5d reduced the cocaine-induced increase in microglial TNFα production (Fig 3E). [1]
Three of eight rats in the 0.1 mg/kg pramipexole vs. 1.0 mg/kg sumanirole or saline failed to meet the training criteria, and the discrimination in this group was tenuous. The D2-preferring antagonist L-741626 at 1.0 mg/kg was more effective at shifting to the right the pramipexole dose-response curve in pramipexole-trained rats, while 32 mg/kg of the selective D3 antagonist PG01037 had little effect. Quinpirole and 7-OH-DPAT fully or partially substituted for both pramipexole and sumanirole in each group tested, while cocaine did not substitute in any group. Conclusions: Antagonist data along with the pattern of training and substitution data suggested that D2 receptor activation is primarily responsible for the stimulus effects of both sumanirole and pramipexole with D3 receptor activation playing little or no role [3].

Four groups of eight rats were trained to discriminate either 0.1 mg/kg of the D3-preferring agonist pramipexole from saline, 1.0 mg/kg of the D2-preferring agonist sumanirole from saline, 0.1 mg/kg pramipexole from either saline or 1.0 mg/kg sumanirole, or 1.0 mg/kg sumanirole from either saline or 0.1 mg/kg pramipexole.

L-741,626 was dissolved in sterile saline except L-741,626, which was dissolved in 5% ethanol, and PG01037, which was dissolved in 20% β-cyclodextrin. All drugs were administered subcutaneously in a volume of 1.0 ml/kg.[3]

Each daily session began with the illumination of both nose-poke holes. Subjects were trained to respond on a fixed ratio (FR) 1 schedule of reinforcement on the left or right nose-poke holes on alternating days, with the opposite hole remaining inactive. The FR was gradually increased to FR 15, and the response requirement reset to the FR value if the rat switched nose-poke holes before completing a ratio. During training sessions, an FR completion on the injection-appropriate hole resulted in 10-s access to 50 μl Ensure (vanilla flavor, delivered undiluted), followed by a 15-s timeout. An FR completion in the opposite hole led to the 15-s timeout only. Test sessions were identical, except a completed FR in either hole led to 10-s access to Ensure. Sessions ended after 20 trials or 20 min, whichever occurred first. If responding was such that all 20 trials resulted in the presentation and consumption of an Ensure delivery, up to 1 ml of Ensure could be earned per session.
Injections were given 5 min prior the start of each session, and the rat was immediately placed in a darkened chamber. Antagonist pretreatments, where applicable, were given 30 min prior to the initiation of a session (25 min prior to the agonist or saline injection and the rat being placed in the darkened chamber). Training conditions differed in each of four groups and are detailed in Table 1. Two groups were trained to discriminate a single drug from saline: 0.1 mg/kg pramipexole from saline or 1.0 mg/kg sumanirole from saline. The other two groups were trained on an either/or procedure, in which one nose-poke hole was associated with two different injections. One of these groups was trained to discriminate 0.1 mg/kg pramipexole from a rotation of 1.0 mg/kg sumanirole and saline, and the other group was trained discriminate 1.0 mg/kg sumanirole from a rotation of 0.1 mg/kg pramipexole and saline. To minimize the probability of side biases developing, the sequence of training days in all four groups was arranged such that the injection-associated nose-poke hole switched from left to right or vice versa each training session. In the either/or groups, this resulted in fewer training sessions with two of the injections, but an equal number of sessions with the left and right nose-poke responses being reinforced.[3]

[1]. Microglial TNF-α Suppresses Cocaine-Induced Plasticity and Behavioral Sensitization. Neuron. 2016 May 4;90(3):483-91.
[2]. Analogues of the dopamine D2 receptor antagonist L741,626: Binding, function, and SAR. Bioorg Med Chem Lett. 2007 Feb 1;17(3):745-9.
[3]. The discriminative stimulus effects of dopamine D2- and D3-preferring agonists in rats. Psychopharmacology (Berl). 2009 Apr;203(2):317-27.
[4]. 3-((4-(4-Chlorophenyl)piperazin-1-yl)-methyl)-1H-pyrrolo-2,3-b-pyridine: an antagonist with high affinity and selectivity for the human dopamine D4 receptor. J Med Chem. 1996 May 10;39(10):1941-2.

4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)-4-piperidinol is a member of piperidines.

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Repeated administration of cocaine results in the development of behavioral sensitization, accompanied by a decrease in excitatory synaptic strength in the nucleus accumbens (NAc) through an unknown mechanism. Furthermore, glial cells in the NAc are activated by drugs of abuse, but the contribution of glia to the development of addictive behaviors is unknown. Tumor necrosis factor alpha (TNF-α), an inflammatory cytokine released by activated glia, can drive the internalization of synaptic AMPA receptors on striatal medium spiny neurons. Here we show that repeated administration of cocaine activates striatal microglia and induces TNF-α production, which in turn depresses glutamatergic synaptic strength in the NAc core and limits the development of behavioral sensitization. Critically, following a period of abstinence, a weak TLR4 agonist can reactivate microglia, increase TNF-α production, depress striatal synaptic strength, and suppress cocaine-induced sensitization. Thus, cytokine signaling from microglia can regulate both the induction and expression of drug-induced behaviors. [1]

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A series of analogues of the dopamine D2 receptor antagonist L-741626 were synthesized and evaluated for binding and function at D2 family receptor subtypes. Several analogues showed comparable binding profiles to the parent ligand, however, in general, chemical modification served to reduce D2 binding affinity and selectivity. [2]

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Rationale: Previous research has found the stimulus effects of dopamine D2- and D3-preferring agonists difficult to distinguish in drug discrimination studies. Antagonism studies suggest that the stimulus effects of both types of agonists may be mediated primarily through D2 receptors. Objectives: The current study was designed to further assess the receptors mediating the stimulus effects of these agonists and to attempt to train rats to discriminate directly between D2- and D3-preferring dopamine agonists. Materials and methods: Four groups of eight rats were trained to discriminate either 0.1 mg/kg of the D3-preferring agonist pramipexole from saline, 1.0 mg/kg of the D2-preferring agonist sumanirole from saline, 0.1 mg/kg pramipexole from either saline or 1.0 mg/kg sumanirole, or 1.0 mg/kg sumanirole from either saline or 0.1 mg/kg pramipexole. Results: Three of eight rats in the 0.1 mg/kg pramipexole vs. 1.0 mg/kg sumanirole or saline failed to meet the training criteria, and the discrimination in this group was tenuous. The D2-preferring antagonist L-741626 at 1.0 mg/kg was more effective at shifting to the right the pramipexole dose-response curve in pramipexole-trained rats, while 32 mg/kg of the selective D3 antagonist PG01037 had little effect. Quinpirole and 7-OH-DPAT fully or partially substituted for both pramipexole and sumanirole in each group tested, while cocaine did not substitute in any group. Conclusions: Antagonist data along with the pattern of training and substitution data suggested that D2 receptor activation is primarily responsible for the stimulus effects of both sumanirole and pramipexole with D3 receptor activation playing little or no role. [3]

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It is widely accepted that the dopaminergic system plays a key role in the manifestation of schizophrenic illness, 1 a belief supported by the observation that all clinically effective antipsychotic agents act as antagonists at the dopamine D2 receptor 2 and that therapeutically relevant plasma concentrations of drug correlate closely to their affinity for this site. 3 Although classical neuroleptics such as haloperidol 1 constitute first-line antipsychotic therapy, their use is associated with severe, mechanism-related side effects including induction of acute extrapyramidal symptoms (EPS), tardive dyskinesia, and problems such as galactorrhea due to increased prolactin release. 4 In contrast, atypical antipsychotics such as clozapine 2 present a lower incidence of EPS, are effective in patients who are unresponsive to classical agents and may also offer advantages in treating the more resistant negative symptoms of schizophrenia. 5 The use of clozapine has, however, been compromised by a relatively high (up to 2%) incidence of the potentially fatal blood disorder agranulocytosis, 6 necessitating stringent monitoring of plasma levels. The high affinity of clozapine for a wide range of neurotransmitter receptors has frustrated attempts to rationalize the improved clinical properties of this drug. 7 It has been postulated that a combination of D2 and 5-HT2 antagonism is responsible for the beneficial properties of atypical neuroleptics, 8 and compounds with this profile, which will serve to support the hypothesis, are now emerging. 9 However, alternative approaches have also been proposed, 10 and the absence of a well-defined, unequivocal mechanism of action for clozapine has hitherto hampered the development of superior antipsychotic agents.[4]

C20H21CLN2O

340.85

340.134

C, 70.48; H, 6.21; Cl, 10.40; N, 8.22; O, 4.69

81226-60-0

133633

White to off-white solid powder

1.311g/cm3

548.8ºC at 760 mmHg

285.7ºC

1.686

4.242

2

2

3

24

416

0

ClC1C=CC(C2(CCN(CC3C4C(=CC=CC=4)NC=3)CC2)O)=CC=1

LLBLNMUONVVVPG-UHFFFAOYSA-N

InChI=1S/C20H21ClN2O/c21-17-7-5-16(6-8-17)20(24)9-11-23(12-10-20)14-15-13-22-19-4-2-1-3-18(15)19/h1-8,13,22,24H,9-12,14H2

4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)piperidin-4-ol

L741,626; L 741,626; L-741,626; L-741626; L 741626; 3-(4-(4-Chlorophenyl-4-hydroxypiperidino)methyl)indole; 4-(4-chlorophenyl)-1-(1h-indol-3-ylmethyl)piperidin-4-ol; 4-(4-Chlorophenyl)-1-(1H-indol-3-ylmethyl)-4-piperidinol; 4-Piperidinol, 4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)-; ...; 81226-60-0; L-741,626

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~146.69 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.33 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.33 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.33 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)