JL 13, An Atypical Antipsychotic: A Preclinical Review

Abstract

The extensive pharmacological evaluation of JL 13 as an atypical antipsychotic drug has revealed a close similarity to clozapine, however with some major advantages. JL 13 was characterized as a weak D 2 antagonist, both in vitro and in vivo, with a strong affinity for the D 4 and the 5-HT 2A receptors. It has no affinity for the 5-HT 2C receptor. In vivo microdialysis experiments in rat showed that JL 13, like clozapine, preferentially increased extracellular dopamine concentrations in the prefrontal cortex compared to nucleus accumbens or striatum.Behavioral studies showed that JL 13, like clozapine, has the profile of an atypical antipsychotic. Thus, JL 13 did not antagonize apomorphine-induced stereotypy nor did it produce catalepsy, but it antagonized apomorphine-induced climbing in rodents. It was inactive against d-amphetamine-induced stereotypy but antagonized d-amphetamine-induced hyperactivity in the mouse. Likewise, in the paw test, it was more effective in prolonging hindlimb retraction time than prolonging forelimb retraction time. Like other antipsychotic drugs, JL 13 reversed the apomorphine-and amphetamine-induced disruption of prepulse inhibition. In a complex temporal regulation schedule in the dog, JL 13 showed a high resemblance with clozapine without inducing sialorrhea, palpebral ptosis or any significant motor side effects. In rats and squirrel monkeys JL 13 induced a high degree of generalization (70%) to clozapine.Regarding behavioral toxicology, JL 13 did not produce dystonia or Parkinsonian symptoms in haloperidol-sensitized monkeys. After acute administration, again like clozapine, JL 13 induced only a transient increase in circulating prolactin. Last but not the least, regarding a possible hematological toxicity, unlike clozapine, JL 13 did not present sensitivity to peroxidase-induced oxidation. Moreover, its electrooxidation potential was close to that of loxapine and far from that of clozapine. Taking all these preclinical data into account, it appears that JL 13 is a promising atypical antipsychotic drug.

Characterization of the effects of receptor-selective ligands in rats discriminating the novel antipsychotic quetiapine

“…Regardless of the resolution of the "scopolamine paradox", the discrimination of drugs such as clozapine and quetiapine can be used as pre-clinical bioassays for detecting in vivo novel drugs which resemble clozapine and related agents (see Bruhwyler et al 1997;Millan et al , 2000Ellenbroek and Liegois 2003), and for dissociating such drugs from older antipsychotics. It remains to be determined to what extent such assays generate false positive antipsychotics (e.g.…”

Long-term Effects of JL 13, a Potential Atypical Antipsychotic, on Ionotropic Glutamate Receptors

“…JL 13 [(5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b] [1,5]benzoxazepine fumarate] is a novel clozapine-like compound that shares with clozapine its high affinity for 5-HT 2A over D 2 receptors (Ellenbroek and Liégeois 2003). Neurochemical studies reported that JL 13 shared similar neurochemical actions with clozapine and other atypical antipsychotics, in terms of their ability to selectively increase dopamine levels in prefrontal cortex in a dosedependent fashion without altering concentrations of dopamine or its metabolites in caudate-putamen (CPu) (Invernizzi et al 2000).…”

Flow and Microwave Induced Pellizzari Reactions: Synthesis of Heterocyclic Analogues of the Benzoxazepine Antipsychotic Agents Loxapine and JL-13

“…The solvents were removed under reduced pressure and the crude product was purified by silica gel chromatography (CH 2 Cl 2 , with 1-10% MeOH gradient). [3,2-f] [1,4]oxazepine. To a cooled solution of 2 (1.08 g, 5.08 mmol) in dry toluene (10 mL) POCl 3 was added (1.42 mL, 15.26 mmol) in a 50 mL round bottom flask under an atmosphere of argon followed by N,Ndimethylaniline (2.57 mL, 20.32 mmol).…”

“…141. [1,4]oxazepine (0.14 g, 0.61 mmol, 1 eq) and hydrazide (0.61 mmol, 1 eq) were dissolved in 1-butanol (3 mL) in a 10 mL glass microwave tube. The vial was capped with a CEM corp. PL cap (SP1318A) and stirred in the cavity of a CEM Discover5 Lab Mate reactor set at 200 ∘ C for 15 min (300 W, 250 psi).…”

“…Prominent examples include the anxiolytic Alprazolam (Xanax5), Loxapine, and the atypical antipsychotic JL13, which has been investigated as a next-generation clozapine analogue [3][4][5]. One of the pharmacologic targets of the agents is the 5-HT 2a receptor, and a number of heterocyclic analogues demonstrate high affinity including Asenapine which despite its altered geometry compares favorably to traditional agents Loxapine and Clozapine [6] (see Scheme 1).…”