Peripheral 5‐HT₂‐like receptors. Can they be classified with the available antagonists?

Abstract

1 Interactions between 5-hydroxytryptamine (5-HT) and the so-called 5-HT2 receptor antagonists ketanserin, spiperone, trazodone and methysergide were studied in isolated preparations of the rabbit aorta, rat jugular vein, and rat caudal artery. 2 Trazodone and spiperone were apparently simple competitive antagonists since they produced antagonism that was surmountable over the concentration range studied and, in each tissue, their apparent affinity appeared to be independent of the antagonist concentration. Furthermore, concentration-ratios obtained with the two antagonists in combination suggested that antagonism was additive, implying mutual competition with a single population of 5-HT receptors. 3 Ketanserin was a non-surmountable antagonist of 5-HT in the rat caudal artery and methysergide demonstrated surmountable, competitive antagonism only in the rabbit aorta. 4 Antagonist dissociation constants estimated for apparently competitive interactions showed that ketanserin, spiperone and trazodone expressed affinities which differed according to the tissue used. In the case of trazodone, affinity estimates differed by as much as 12 fold. These discrepancies were independent of the 5-HT receptor agonist used and could not be attributed to an inadequate equilibration of the antagonist. 5These results can be interpreted in two ways: either the receptors in the different tissues are heterogeneous or the antagonists used here must be considered as unreliable probes for the classification of 5-HT2-like receptors.

Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

“…As usual for such organ bath experiments (Leff and Martin, 1986), the tissues were preincubated with the antagonist before their challenge with agonist. Antagonists that inhibit the maximal response under such conditions are referred to as insurmountable (Gaddum et al, 1955;Vauquelin et al, 2002a,b).…”

Heterogeneity of thromboxane A2 (TP‐) receptors: evidence from antagonist but not agonist potency measurements

“…It seems more likely that small variations in the accessory binding sites for antagonists (say the substitution of a single amino acid) could account for the affinity differences: these structural differences would have minimal effect on the potencies of the full and partial agonists. Leff & Martin (1986) have discussed similar propositions in relation to the characterisation of 5-HT2-like receptors and have raised the question as to whether antagonists chemically related to the natural agonist are of more use in defining subtypes as opposed to antagonists which bear little chemical relation. It is of interest that in our studies, the TP-receptor antagonist which is least prostanoid-like in structure, BM 13177 (Patscheke & Stegmeier, 1984), shows least variation in antagonist affinity.…”

Differences in agonist dissociation constant estimates for 5‐HT at 5‐HT2‐receptors: a problem of acute desensitization?

“…Operational modelfitting The averaged E/[A] curve data measured in g force were fitted directly to the operational model of agonism (Black & Leff, 1983;Black et al, 1985;Leff et al, 1986):…”

“…which is the transducer relation assumed in the operational model of agonism (Black & Leff, 1983;Black et al, 1985;Leff et al, 1986). Thus, effect-time profiles corresponding to different values of k1, k 1, k2 etc.…”

“…In a number of recent articles (Leff & Martin, 1986;Leff et al, 1986;Martin et al, 1987) we have considered the use of tryptamine analogues in 5-hydroxytryptamine (5-HT) receptor classification. Essentially, these articles addressed the extent to which quantitative pharmacological information, namely affinity and efficacy estimates, can be obtained in isolated tissue assays, and the implications that this information has for 5-HT receptor classification in the context of information obtained using non-tryptamine 5-HT receptor ligands.…”