The Second-generation Antagonist, GR 82334

2018-09-21

Introduction 

GR 82334 is a spirolactam analog with the structure of [[(S, S) Pro-Leu (spiro-γ-lactam)]9,10, Trp11] Physalaemin (1-11) that exhibits selective tachykinin NK1 receptor antagonism. NK1 receptor is widely distributed in the central and peripheral nervous systems and is distributed in neurons, brainstem, vascular endothelial cells, muscle, gastrointestinal tract, genitourinary tract, lung tissue, thyroid and various immune cells. GR 82334 is a 3-Amino-γ-lactams, which bears simple alkyl 3-position substituents and a 1,7-diazaspiro [4,4] nonan-6-one scaffold that has been used in medicinal chemistry programs. As the second-generation antagonist, GR 82334 has improved enzyme stability and selectivity.

Biological Activity

Tachykinins, a family member of neuropeptides, are widely distributed throughout the mammalian central and peripheral nervous system. Three receptors for tachykinins have been characterized: neurokinin-1 (NK1), NK2 and NK3, for which SP neurokinin A and neurokinin B possess preferential but not exclusive affinity, respectively. In an ex vivo human tonsil tissue proliferation assay, GR 82334 was used to study the role of the "Substance P"-NK1 pathway in pediatric obstructive sleep apnea, highlighting potential for an underexploited non-surgical intervention. GR 82334 can completely antagonize the cyclophosphamide-induced decrease in the volume threshold for micturition, and also reduce the micturition frequency in the rats with hyperreflexia during chemical cystitis in anaesthetized rats. The effect of GR 82334 on reflex-induced bladder contractions in rat shows that contrary to several substance P antagonists of first generation, the administration of GR 82334 is not accompanied by motor disturbances/neurotoxic effects at doses producing analgesia.

Function

The neurokinin receptor NK1 receptor and substance P (SP) have the highest selectivity and the strongest binding ability, so it is also called SP receptors, and it is widely distributed in both the central and peripheral nervous system. The pharmacological effects of SP are associated with the pathophysiology of a variety of neurological and psychiatric disorders such as migraine, asthma, nausea, enteritis syndrome, urinary incontinence, anxiety and depression. NK1RA, such as GR 8233, has antidepressant and anti-anxiety effects, also has a good therapeutic effect on chemotherapy-induced nausea and vomiting. Combined with anti-emetic drugs, it can better control delayed vomiting and postoperative vomiting

References:

1. Alessandro Lecci, Sandro Giuliani, et al. Involvement of spinal tachykinin NK 1 and NK 2 receptors in detrusor hyperreflexia during chemical cystitis in anaesthetized rats. European Journal of Pharmacology, 1994, 259, 129-135.

2. Riccardo Patacchini, Sandro Giuliani, et al. Effect of nepadutant at tachykinin NK2 receptors in human intestine and urinary bladder. European Journal of Pharmacology, 2000, 398, 389-397.

3. Sabine Böckmanna, Janka Seepa, Ludwig Jonasb. Delay of neutrophil apoptosis by the neuropeptide substance P: involvement of caspase cascade. Peptides, 2001, 22, 661-670.

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