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Corticotropin-releasing factor (CRF) is a neuropeptide hormone which is secreted from the paraventricular nucleus of the hypothalamus and regulates the body's overall response to stress. It is the main regulator of the hypothalamus–pituitary–adrenocortical (HPA) axis. Numerous disorders including anxiety, depression, addictive disorders, Irritable Bowel Syndrome (IBS), cardiovascular diseases, and several other disorders of the immune system, as well as the reproductive system, are related to over activation of the CRF system. CRF exerts its action by binding to CRF receptors, especially CRF₁ receptors. The involvement of CRF and its receptors in the CNS suggests that the molecules which can interfere with CRF functions and CRF binding to its receptors may be potential candidates for neuropsychiatric drugs to treat stress-related disorders.
Previously, a few series of pyrimidine and fused pyrimidine CRF₁R antagonists were synthesized and biologically evaluated by our group. In continuation of our effort to develop CRF₁ receptors antagonist with superior binding affinity, a series of new compounds was synthesized as CRF₁R antagonist and biologically evaluated by two different assays including a specific binding assay and a competitive binding study on HEK-293 cells express human CRF₁ receptors.
Among the compounds of the new series, five compounds showed promising binding affinity to CRF₁receptors where the best compound has Log ki ± SE values of -7.39 ± 0.09 compared to standard drug antalarmin Log ki ± SE values is -8.01 ± 0.24. It is worth mentioning that the best compound of this new series (compound 6) showed superior binding affinity to CRF₁ receptors to all of our previously synthesized compounds. It has only four times less binding affinity than the standard CRF₁ antagonist antalarmin, which is a great improvement since our previous compounds had 10 times less binding affinity than antalarmin.

MD RABIUL ISLAM

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