Characterization of 5-hydroxytryptamine receptors in rat stomach fundus.
1-Arylpiperazines (MK-212, quipazine, m-chlorophenylpiperazine and m-trifluoromethylphenylpiperazine) caused a serotonin (5-HT) receptor-mediated contraction of rat fundic strips. m-chlorophenylpiperazine and m-trifluoromethylphenylpiperazine had high affinity for the receptor but little efficacy, whereas quipazine and MK-212 had lesser affinity and much greater efficacy. 5-HT itself was the most potent (EC50 = 6-9 nM) agonist and possessed the greatest affinity (KA = 9.7 nM). Assessment of receptor occupancy vs. functional response (as well as receptor alkylation studies) demonstrated a very small, if any, receptor reserve in this tissue. Several arylquinolizines were found to be competitive antagonists of 5-HT-induced contraction, the most potent being L-653,267 and rauwolscine (KB values = 1.9 and 3.8 nM). Clozapine, trazodone and propranolol were identified as less potent, competitive antagonists, whereas various ergolines (including LY 53857), L-646,462 (cyproheptadine analog) and mianserin were noncompetitive. Potent 5-HT2 receptor antagonists (pirenpirone and ketanserin) antagonized only weakly or were without effect against 5-HT, indicating that the fundic 5-HT receptor is not of the 5-HT2 subtype. Because the fundic receptor has high affinity for 5-HT (as does the 5-HT1 binding site in brain tissue), the possible correspondence of the fundic 5-HT receptor with the 5-HT1 recognition site in rat brain cortex was considered. 5-HT, the nonindole agonists (1-arylpiperazines) and the competitive antagonists all competed with [3H]-5-HT for the 5-HT1 site. However, all compounds except 5-HT had Hill slopes significantly less than 1.0, precluding a valid comparison with dissociation constants derived pharmacologically in the fundus. With respect to having a high affinity for 5-HT, the 5-HT receptor mediating contraction of fundic smooth muscle resembles the 5-HT1 recognition site (as defined in brain tissue by radioligand binding), but identity remains unproven.
D000818:Animals; D001667:Binding, Competitive; D001923:Brain Chemistry; D005748:Gastric Fundus / Q000032:analysis* / Q000187:drug effects; D066298:In Vitro Techniques; D007650:Ketanserin; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D011814:Quipazine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000032:analysis* / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology; D014316:Tritium
D010879:Piperazines; D010880:Piperidines; D011719:Pyrazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D014316:Tritium; C018406:1-(3-trifluoromethylphenyl)piperazine; D012701:Serotonin; D011814:Quipazine; C014896:6-chloro-2-(1-piperazinyl)pyrazine; D007650:Ketanserin; D011433:Propranolol; C015068:1-(3-chlorophenyl)piperazine