Synthesis and binding affinity of new pyrazole and isoxazole derivatives as potential atypical antipsychotics (original) (raw)
Related papers
Bioorganic & Medicinal Chemistry Letters, 1995
Starting from 2-methyl-3-ethyl-lH-4,5,6,7-tetrahydroindol4one 3 we have prepared 2-methyl-3ethyl-5-morpholinoethyl-1H-4,5,6,7-tetmhydroindol4one. (1) and 2-methyl-3-ethyl-5-(4-o-methoxyphenyl-lpiperazinoethyl)-lH-4,5.6,7-tetrahydroindol-4-one (2) as butyrophenone analogues of the neuroleptic molindone. The affinities of these compounds for Dt and D2 dopamine and 5HT2A serotonin receptors were evaluated in vitro. The affinity of 1 for 9 receptors is less than that of molindone (pKi's 6.23 and 7.48 respectively) and that of 2 similar (pKt 7.55). Roth compounds bind to 5HTw receptors, the affinity of 2 being significantly greater than that of molindone (p&Is of 7.04 and 5.85, and PAZ'S of 7.50 and 6.18. respectively). Several aminoketones possess potent antipsychotic (netuoleptic) activity: molindonet, first marketed in the USA in 1974, has been used in the treatment of schizophrenia and psychosis, but its associated incidence of extrapyramidal side effects (EPS) is significant; the pyrtolo[2,3-glisoquinoline piquindone (Ro 22-1319)2 is an antipsychotic with a low propensity to induce EPS; and haloperidol is the prototype of a group of butyrophenone derivatives with very potent antipsychotic activity, among them the most potent neuroleptics, spiperone and fluanisone, which are 4-amino-pfluorobutyrophenone derivatives. The clinical efficacy of classical antipsychotics in the treatment of schizophrenia and other psychotic disorders is directly related to their ability to block dopamine 9 receptors in the brat@; however, it has been reported that dopamine receptor blockade in the striatum is closely associated with their extrapyramidal side effects m. Furthermore, the classical antipsychotics are ineffective against negative symptoms of schizophrenia such as apathy, motor retardation. flat affectivity and poverty of speech.
Bioorganic & Medicinal …, 2010
We described herein the design, synthesis, and pharmacological evaluation of N-phenylpiperazine heterocyclic derivatives as multi-target compounds potentially useful for the treatment of schizophrenia. The isosteric replacement of the heterocyclic ring at the biaryl motif generating pyrazole, 1,2,3-triazole, and 2-methylimidazole[1,2-a]pyridine derivatives resulted in 21 analogues with different substitutions at the para-biaryl and para-phenylpiperazine positions. Among the compounds prepared, 4 (LASSBio-579) and 10 (LASSBio-664) exhibited an adequate binding profile and a potential for schizophrenia positive symptoms treatment without cataleptogenic effects. Structural features of this molecular scaffold are discussed regarding binding affinity and selectivity for D 2-like, 5-HT 1A , and 5-HT 2A receptors.
Journal of Medicinal Chemistry, 2004
Recently we reported the pharmacological characterization of the 9,10-dihydropyrrolo[1,3]benzothiazepine derivative (S)-(+)-8 as a novel atypical antipsychotic agent. This compound had an optimum pK i 5-HT 2A /D 2 ratio of 1.21 (pK i 5-HT 2A) 8.83; pK i D 2) 7.79). The lower D 2 receptor affinity of (S)-(+)-8 compared to its enantiomer was explained by the difficulty in reaching the conformation required to optimally fulfill the D 2 pharmacophore. With the aim of finding novel atypical antipsychotics we further investigated the core structure of (S)-(+)-8, synthesizing analogues with specific substituents; the structure-activity relationship (SAR) study was also expanded with the design and synthesis of other analogues characterized by a pyrrolo[2,1-b][1,3]benzothiazepine skeleton, substituted on the benzo-fused ring or on the pyrrole system. On the 9,10-dihydro analogues the substituents introduced on the pyrrole ring were detrimental to affinity for dopamine and for 5-HT 2A receptors, but the introduction of a double bond at C-9/10 on the structure of (S)-(+)-8 led to a potent D 2 /5-HT 2A receptor ligand with a typical binding profile (9f, pK i 5-HT 2A /D 2 ratio of 1.01, log Y) 8.43). Then, to reduce D 2 receptor affinity and restore atypicality on unsaturated analogues, we exploited the effect of specific substitutions on the tricyclic system of 9f. Through a molecular modeling approach we generated a novel series of potential atypical antipsychotic agents, with optimized 5HT 2A /D 2 receptor affinity ratios and that were easier to synthesize and purify than the reference compound (S)-(+)-8. A number of SAR trends were identified, and among the analogues synthesized and tested in binding assays, 9d and 9m were identified as the most interesting, giving atypical log Y scores respectively 4.98 and 3.18 (pK i 5-HT 2A /D 2 ratios of 1.20 and 1.30, respectively). They had a multireceptor affinity profile and could be promising atypical agents. Compound 9d, whose synthesis is easier and whose binding profile is atypical (log Y score similar to that of olanzapine, 3.89), was selected for further biological investigation. Pharmacological and biochemical studies confirmed an atypical antipsychotic profile in vivo. The compound was active on conditioned avoidance response at 1.1 mg/kg, a dose 100-times lower than that required to cause catalepsy (ED 50 >90 mg/kg), it induced a negligible increase of prolactin serum levels after single and multiple doses, and antagonized the cognitive impairment induced by phencyclidine. In conclusion, the pharmacological profile of 9d proved better than clozapine and olanzapine, making this compound a potential clinical candidate.
European Journal of Medicinal Chemistry, 2003
A series of novel conformationally restricted butyrophenones (6-aminomethyl-4,5,6,7-tetrahydrobenzo[b]furan-4-ones bearing 4-(6-fluorobenzisoxazolyl)piperidine, 4-(p-fluorobenzoyl)piperidine, 4-(o-methoxyphenyl)piperazine, 4-(2-pyridyl)piperazine, 4-(2-pyrimidinyl)piperazine, or linear butyro(or valero)phenone fragments) were prepared and evaluated as antipsychotic agents by in vitro assays for affinity for dopamine receptors (D 1 , D 2 , D 4) and serotonin receptors (5-HT 2A , 5-HT 2B , 5-HT 2C), by neurochemical studies, and by in vivo assays for antipsychotic potential and the risk of inducing extrapyramidal side effects. Potency and selectivity depended mainly on the amine fragment connected to the cyclohexanone structure. Compounds 20b, with a benzoylpiperidine moiety, and 20c, with a benzisoxazolyl fragment, were selective for 5-HT 2A receptors. The in vitro and in vivo pharmacological profiles of N-[(4-oxo-4,5,6,7-tetrahydrobenzo-[b]furan-6-yl)methyl]-4-(p-fluorobenzoyl)piperidine (20b, QF1003B) and N-[(4-oxo-4,5,6,7-tetrahydrobenzo[b]furan-6-yl)methyl]-4-(6-fluorobenzisoxazol-3-yl)piperidine (20c, QF1004B) suggest that they may be effective as antipsychotic (neuroleptic) drugs. § This is the 22nd paper in the series "Synthesis and CNS Activity of Conformationally Restricted Butyrophenones"; for preceding papers, see ref 47.
Bioorganic & Medicinal Chemistry Letters, 2009
A series of 8 new tetrahydroquinazolinone derivatives was synthesized and evaluated for binding affinity to D 2 and 5-HT 2A human receptors; in addition, some properties related to blood-brain barrier penetration were calculated. From the results of these assays, three compounds were selected for further binding tests on D 1 , D 3 , and 5-HT 2C human receptors, which are thought to be involved in schizophrenia. From these data, compound 19b emerged as the most promising candidate based on its good binding affinities for D 1 , D 2 , and D 3 receptors, high affinity for 5-HT 2A , low affinity for 5-HT 2C receptors, and a Meltzer's ratio characteristic of an atypical antipsychotic profile.
Journal of Medicinal Chemistry, 2002
The prototypical dopamine and serotonin antagonist (()-7-chloro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine (5) was resolved into its R and S enantiomers via crystallization of the diastereomeric tartaric acid salts. Binding studies confirmed that the (R)-(-)-enantiomer is a more potent D 2 receptor antagonist than the (S)-(+)-enantiomer, with almost identical affinity at the 5-HT 2 receptor ((S)-(+)-5, log Y) 4.7; (R)-(-)-5, log Y) 7.4). These data demonstrated a significant stereoselective interaction of 5 at D 2 receptors. Furthermore, enantiomer (S)-(+)-5 (ST1460) was tested on a panel of receptors; this compound showed an intriguing binding profile characterized by high affinity for H 1 and the R 1 receptor, a moderate affinity for R 2 and D 3 receptors, and low affinity for muscarinic receptors. Pharmacological and biochemical investigation confirmed an atypical pharmacological profile for (S)-(+)-5. This atypical antipsychotic lead has low propensity to induce catalepsy in rat. It has minimal effect on serum prolactin levels, and it has been selected for further pharmacological studies. (S)-(+)-5 increases the extracellular levels of dopamine in the rat striatum after subcutaneous administration. By use of 5 as the lead compound, a novel series of potential atypical antipsychotics has been developed, some of them being characterized by a stereoselective interaction at D 2 receptors. A number of structure-activity relationships trends have been identified, and a possible explanation is advanced in order to account for the observed stereoselectivity of the enantiomer of (()-5 for D 2 receptors. The molecular structure determination of the enantiomers of 5 by X-ray diffraction and molecular modeling is reported.
Neuropharmacology, 2006
The aim of the present work was to characterize a lead compound displaying relevant multi-target interactions, and with an in vivo behavioral profile predictive of atypical antipsychotic activity. Synthesis, molecular modeling and in vitro and in vivo pharmacological studies were carried out for 2-[4-(6-fluorobenzisoxazol-3-yl)piperidinyl]methyl-1,2,3,4-tetrahydro-carbazol-4-one (QF2004B), a conformationally constrained butyrophenone analogue. This compound showed a multi-receptor profile with affinities similar to those of clozapine for serotonin (5-HT 2A , 5-HT 1A , and 5-HT 2C ), dopamine (D 1 , D 2 , D 3 and D 4 ), alpha-adrenergic (a 1 , a 2 ), muscarinic (M 1 , M 2 ) and histamine H 1 receptors. In addition, QF2004B mirrored the antipsychotic activity and atypical profile of clozapine in a broad battery of in vivo tests including locomotor activity (ED 50 ¼ 1.19 mg/kg), apomorphine-induced stereotypies (ED 50 ¼ 0.75 mg/kg), catalepsy (ED 50 ¼ 2.13 mg/kg), apomorphine-and DOI (2,5-dimethoxy-4-iodoamphetamine)-induced prepulse inhibition (PPI) tests. These results point to QF2004B as a new lead compound with a relevant multi-receptor interaction profile for the discovery and development of new antipsychotics.
2012
Using haloperidol as a scaffold, new agents were designed to investigate the structural contributions of various groups to binding at CNS receptors associated with atypical antipsychotic pharmacology. It is clear that each pharmacophoric group, the butyrophenone, the piperidine and the 4-chlorophenyl moieties contributes to changes in binding to the receptors of interest. This strategy has resulted in the identification of several new agents, compounds 16, 18, 19, 23, 24 and 25, with binding profiles which satisfy our stated criteria for agents to act as potential atypical antipsychotics. This research demonstrates that haloperidol can serve as a useful lead in the identification and design of new agents that target multiple receptors associated with antipsychotic pharmacology.