title: 5-hydroxyindalpine, an agonist at the putative 5-HT receptor, has no activity on human recombinant monoamine receptors but accelerates distension-induced peristalsis in mouse isolated colon.
abstract: Although the putative 5-HT(1P) receptor has been implicated to have a role in peristalsis, experiments which suggest this function are preliminary or have measured only components of the reflex. We have, therefore, further characterized a reported agonist at this receptor (5-hydroxyindalpine; 5-OHIP) and investigated the effects of 5-OHIP and 5-hydroxytrytophan-dipeptide (5-HTP-DP), a reported 5-HT(1P) receptor antagonist, on distension-induced peristalsis in mouse colon. The effects of 5-OHIP on intracellular calcium, cyclic adenosine monophosphate concentrations or GTPgammaS binding were measured in cell lines expressing human recombinant 5-HT(1A, 1B, 1D, 2A, 2B, 2C, 3, 4, 6, 7) and alpha(1A), alpha(1B), D(1), D(2), D(3), H(1), H(3) receptors. The effects of 5-OHIP and 5-HTP-DP on peristalsis were assessed by measuring changes in frequency and times to reach threshold of peristaltic contractions, as well as the threshold and maximum pressures of each peristaltic stroke. 5-hydroxyindalpine (1 nmol L(-1)-10 micromol L(-1)) had no significant activity at any of the receptors studied. However, 5-OHIP (0.1 nmol L(-1)-1 micromol L(-1)) concentration-dependently increased the frequency of peristalsis (EC(50) = 4.4 nmol L(-1)) and reduced the time taken to reach threshold and threshold pressure, without altering maximum pressures. The maximum effect of 5-OHIP was at 1 micromol L(-1) (68.0 +/- 14.5% increase in frequency); 10 micromol L(-1) decreased peristalsis. 5-hydroxytrytophan-dipeptide (1-300 nmol L(-1)) also increased the frequency of peristalsis and prevented the actions of 5-OHIP. The higher concentration (1 micromol L(-1)) transiently inhibited peristalsis and after recovery, prevented the actions of 5-OHIP but not the excitatory activity of the cholinesterase inhibitor neostigmine. In summary, the present data demonstrate an interaction of '5-HT(1P)-ligands' with the peristaltic reflex. However, the absence of an effect of 5-OHIP on a range of different monoamine receptors continues to highlight the need to investigate the identity of the putative 5-HT(1P) receptor.
authors.affiliation: Immuno Inflammation Centre of Excellence in Drug Discovery, GlaxoSmithKline, Stevenage, UK.
authors.forename: N A
authors.initials: NA
authors.lastname: Mitchell
authors.forename: E
authors.initials: E
authors.lastname: Pepperell
authors.forename: S
authors.initials: S
authors.lastname: Ociepka
authors.forename: J D
authors.initials: JD
authors.lastname: Brown
authors.forename: J
authors.initials: J
authors.lastname: Witherington
authors.forename: B
authors.initials: B
authors.lastname: Tuladhar
authors.forename: G J
authors.initials: GJ
authors.lastname: Sanger
authors.forename: K
authors.initials: K
authors.lastname: Lee
authors.forename: S
authors.initials: S
authors.lastname: Cellek
mesh_terms: D000818:Animals; D003106:Colon / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D008365:Manometry; D051379:Mice; D009924:Organ Culture Techniques; D010528:Peristalsis / Q000187:drug effects* / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014162:Transfection
chemical_list: D010880:Piperidines; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D017366:Serotonin Receptor Agonists; C059798:5-hydroxyindalpine