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.2009 Jan;91(3):307-14.
doi: 10.1016/j.pbb.2008.07.015. Epub 2008 Jul 30.

Pharmacological properties and discriminative stimulus effects of a novel and selective 5-HT2 receptor agonist AL-38022A [(S)-2-(8,9-dihydro-7H-pyrano[2,3-g]indazol-1-yl)-1-methylethylamine]

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Pharmacological properties and discriminative stimulus effects of a novel and selective 5-HT2 receptor agonist AL-38022A [(S)-2-(8,9-dihydro-7H-pyrano[2,3-g]indazol-1-yl)-1-methylethylamine]

Jesse A May et al. Pharmacol Biochem Behav.2009 Jan.

Abstract

AL-38022A is a novel synthetic serotonergic (5-HT) ligand that exhibited high affinity for each of the 5-HT2 receptor subtypes (Ki<or=2.2 nM), but a significantly lower (>100-fold less) affinity for other 5-HT receptors. In addition, AL-38022A displayed a very low affinity for a broad array of other receptors, neurotransmitter transport sites, ion channels, and second messenger elements, making it a relatively selective agent. AL-38022A potently stimulated functional responses via native and cloned rat (EC50 range: 1.9-22.5 nM) and human (EC50 range: 0.5-2.2 nM) 5-HT2 receptor subtypes including [Ca2+]i mobilization and tissue contractions with apparently similar potencies and intrinsic activities and was a full agonist at all 5-HT2 receptor subtypes. The CNS activity of AL-38022A was assessed by evaluating its discriminative stimulus effects in both a rat and a monkey drug discrimination paradigm using DOM as the training drug. AL-38022A fully generalized to the DOM stimulus in each of these studies; in monkeys MDL 100907 antagonized both DOM and AL-38022A. The pharmacological profile of AL-38022A suggests that it could be a useful tool in defining 5-HT2 receptor signaling and receptor characterization where 5-HT may function as a neurotransmitter.

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Figures

Figure 1
Figure 1
Chemical structure of AL-38022A.
Figure 2
Figure 2
Percent drug-appropriate responding (± S.E.M.) following administration of AL-38022A,R-DOI, DOM, and 5-OMe DMT to rats (n = 6–9) trained to discriminate 1.0 mg/kg of DOM from saline vehicle (saline = 5 ± 2%) is shown in the upper panel. Response rate is shown in the lower panel (saline = 13.1 ± 3.1 responses/min).
Figure 3
Figure 3
Percent drug-appropriate responding (± S.E.M.) following administration of AL-38022A,R-DOI and DOM to rhesus monkeys (n = 4) trained to discriminate 0.32 mg/kg of DOM from vehicle is shown in the upper panel. Rate of responding is shown in the lower panel in responses per second.
Figure 4
Figure 4
Percent drug-appropriate responding (± S.E.M.) following administration of different doses of MDL 100907 in combination with 0.1 mg/kg AL-38022A or 0.32 mg/kg DOM to rhesus monkeys (n = 4). See Figure 3 for other details. *p < 0.05 compared to either 0.32 mg/kg DOM or 0.1 mg/kg AL-38022A administered alone.
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