Design, synthesis and pharmacological evaluation of active pyrrole based, nonpeptidic analogues of neurotensin(8-13)

Abstract

We report the design, synthesis and pharmacological analysis of pyrrole based, nonpeptidic analogues of neurotensin(8-13) for testing further our reported multiple template approach to developing nonpeptidic mimetics of neuropeptides and for developing nonpeptidic mimetics of neurotensin(8-13) as potential drug candidates for the treatments of neuropsychiatric diseases such as schizophrenia and Parkinson’s disease. Three newly synthesized pyrrole analogues (mimics-4, -5 and -6) designed by the multiple template approach have been found to be more active in binding to the neurotensin receptor than the previously reported indole based mimics-1 and -2, which are a partial nonpeptidic antagonist and an agonist of neurotensin(8-13), respectively. The results support the theory of the multiple template approach and provide insights into the rational design of more potent neurotensin mimetics and into the library design for rational screening for effective nonpeptide compounds by combinatorial chemistry.