Gene/Protein
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Drug
Enzyme
Compound
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Target Concepts:
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Query: UMLS:C0036341 (
schizophrenia
)
60,220
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Neurotensin (NT, pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) is a tridecapeptide that displays a wide spectrum of biological actions. Cyclic derivatives of a hexapeptide NT [(8-13)] (N alpha MeArg-Lys-Pro-Trp-Tle-Leu, Tle = tert-leucine) were designed and prepared by a combination of solution and solid-phase peptide synthetic methodologies. As reported previously, several analogs possessed nanomolar binding affinities for NT receptors in newborn (10-day-old) mouse brain membrane preparations. In this study, we determined the functional ability of these analogs to mobilize intracellular free calcium, [Ca2+]i, in HT-29 cells (human colonic adenocarcinoma). Of greatest interest were the cyclic compounds 2, 6 and 9 that had Ki values of 0.19, 3.50 and 4.18 microM for [3H]NT labeled receptors in the HT-29 cell membrane assay, respectively. In the functional assay, compounds 2 and 6 mobilized [Ca2+] with EC50 values of 0.13 and 20 microM, respectively. In comparison,
Compound 9
blocked the NT-induced mobilization of [Ca2+]i, with an IC50 of 1.70 microM. The present findings indicate that small molecule cyclic analogs, that possess functional activity, can be designed and may have therapeutic utility in the treatment of
schizophrenia
and possibly other neurological disorders.
...
PMID:Functional activity of new C-terminal cyclic-neurotensin fragment analogs. 881 44
Schizophrenia
is a complex disease with not fully understood pathomechanism, involving many neurotransmitters and their receptors. This is why it is best treated with multi-target drugs, such as second generation antipsychotics. Here we present 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles (1-20) which are ligands of dopamine D
2
and serotonin 5-HT
1A
and 5-HT
2A
receptors and display affinity in the nanomolar range. These compounds were designed as modifications of the virtual hit experimentally confirmed, D2AAK1, and synthesized from indole or 5-alkoxyindoles and N-substituted piperidin-4-ones in methanol in the presence of potassium hydroxide.
Compound 9
was subjected to X-ray studies and it crystallizes in the centrosymmetric monoclinic space group P2
1
/c with one molecule in an asymmetric unit. Three most potent compounds (5, 9 and 17) turned out to be antagonists of both D
2
and 5-HT
2A
receptors what is beneficial for their potential application as antipsychotics. Compound 5 was subjected to behavioral studies and exhibited antipsychotic, pro-cognitive and antidepressant activity in appropriate mice models. Structure-activity relationships for compounds 1-20 were rationalized using molecular docking. It was found that, in general, bulky C5-alkoxy substituents at the indole moiety are not favorable as they direct towards aqueous environment of the extracellular vestibule. Keywords: antipsychotics; behavioral studies, G protein-coupled receptors; indole derivatives; multi-target compounds;
schizophrenia
.
...
PMID:Synthesis, pharmacological and structural studies of 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as multi-target ligands of aminergic GPCRs. 3135 29
