ABSTRACT
The synthesis and preliminary structure-activity relationships (SAR) of a novel class of vasopressin V(1B) receptor antagonists are described. Hit compound 5, identified via high throughput screening of the corporate collection, showed good activity in a V(1B) binding assay (K(i) 63 nM) but did not possess the lead-like physicochemical properties typically required in a hit compound. A 'deletion approach' on the HTS hit 5 was performed, with the focus on improvement of physicochemical properties, yielding the selective V(1B) antagonist 9f (K(i) 190 nM), with improved druglike characteristics.
Subject(s)
Antidiuretic Hormone Receptor Antagonists , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Molecular Structure , Protein Binding/drug effects , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
Hypothalamo-pituitary-adrenal (HPA) axis changes have been reported in several disease states, including major depressive disorder, rheumatoid arthritis, multiple sclerosis and various other conditions associated with chronic pain. These observations suggest that stress and the HPA axis may play important roles in the pathology of these diseases. In order to contribute to a better understanding of the role that chronic stress may play in human pathology, this review article explores the involvement of the HPA axis in those animal models of chronic pain and inflammation that entail persistent rather than intermittent stress.
Subject(s)
Hypothalamo-Hypophyseal System/physiology , Inflammation/physiopathology , Pain/physiopathology , Pituitary-Adrenal System/physiology , Stress, Physiological/physiopathology , Animals , Chronic Disease , Disease Models, AnimalABSTRACT
Pain is a multi-dimensional process involving the physical, emotional and perceptual integration of noxious information. The physical component is relayed via the spinal cord to several brain areas to initiate the detection of pain. The emotional aspect is encoded by the limbic system and encapsulates the relationship between pain and mood. Within the limbic system, the hypothalamus undertakes a diversity of separate and interrelated functions. Dysfunction of the hypothalamo-pituitary-adrenal axis has been implicated in a variety of chronic pain conditions and might also be associated with increased risk of developing mood disorders. Experimental and clinical evidence also exists to implicate the effects of other hormonal modulators in the manifestation of chronic pain. Specific targeting of hormonal cascade and effector mechanisms could provide an alternative strategy for the treatment of various chronic pain conditions.
