Conformationally restricted cyclic analogues of substance P: Insight into the receptor binding process

Three new cyclic substance P analogues were prepared to examine the possible role of a pseudocyclic turn structure for receptor recognition. In the guinea pig isolated ileum [Cy over(over(s⁵, C, {top square bracket}),) ys¹¹]-SP_5-11 - NH₂ and [Cy over(over(s⁶, C, {top square bracket}),) ys¹¹]-SP_5-11 - NH₂ were inactive at concentrations up to 100 μM, while [Cy over(over(s⁵, C, {top square bracket}),) ys⁶, Nle¹¹] - SP was a weak agonist. The order of relative affinities on the rat brain radioreceptor assay was as follows: [Cy over(over(s⁵, C, {top square bracket}),) ys⁶, Nle¹¹] - SP> [Cy over(over(s⁵, C, {top square bracket}),) ys¹¹] - SP_5-11 - NH₂ > [Cy over(over(s⁶, C, {top square bracket}),) ys¹¹] - SP_5-11 - NH₂. We interpret these results to indicate that a pseudocyclic structure of the 5-11 sequence may not be an important factor involved in the receptor recognition of substance P.