Characterization of the effect of SR48692 on inositol monophosphate, cyclic GMP and cyclic AMP responses linked to neurotensin receptor activation in neuronal and non‐neuronal cells

1 Neurotensin stimulated inositol monophosphate (IP1) formation in both human colonic carcinoma HT29 cells and in mouse neuroblastoma N1E115 cells with EC50 values of 3.5 ± 0.5 nM (n = 4) and 0.46±0.02 nM (n = 3), respectively. Neurotensin also stimulated cyclic GMP production with an EC50 of 0.47±1.2 nM and inhibited cyclic AMP accumulation induced by forskolin (0.5 μm) with an IC50 of 1.33 + 1.5 nM (n = 3) on the N1E115 cell line 2 The competitive antagonism by the non‐peptide neurotensin receptor antagonist, SR48692 of neurotensin‐induced IP1 formation revealed pA2 values of 8.7 ±0.2 (n = 3) for HT29 and 10.1 ±0.2 (n = 3) for N1E115 cells. SR48692 also antagonized the cyclic GMP and cyclic AMP responses induced by neurotensin in the N1E115 cell line with pA2 values of 10.7±0.7 (n = 3) and 9.8±0.3 (n = 3), respectively 3 In CHO cells transfected with the rat neurotensin receptor, neurotensin stimulated IP1 and cyclic AMP formation with EC50 values of 3.0±0.5 nM (n = 3) and 72.2 ±20.7 nM (n = 3), respectively. Both effects were antagonized by SR48692, giving pA2 values of 8.4 ±0.1 (n = 3) for IP1 and 7.2 ±0.4 (n = 3) for cyclic AMP responses 4 Radioligand binding experiments, performed with [125I]‐neurotensin (0.2 nM), yielded IC50 values of 15.3 nM (n = 2) and 20.4 nM (n = 2) for SR48692 versus neurotensin receptor binding sites labelled in HT29 and N1E115 cells, respectively 5 In conclusion, SR48692 appears to be a potent, species‐independent antagonist of the signal transduction events triggered by neurotensin receptor activation in both neuronal and non‐neuronal cell systems.