Structural influences upon antihistamine activity; 3-amino-1-aryl-1-(2-pyridyl)propenes and related compounds

Abstract

A series of 3‐amino‐1‐aryl‐1‐(2‐pyridyl)propenes and related compounds have been prepared by the dehydration of corresponding tertiary alcohols, and the configurations of geometrical isomeric derivatives established from spectroscopic data. The ability of the aminopropenes to antagonize histamine‐induced contractions of the guinea‐pig ileum is reported. These data allow various structure‐activity relations to be discussed including stereochemistry (cis 2‐pyridyl/H geometry is superior to cis substituted phenyl/H but not necessarily to cis phenyl/H), nature of the basic function (1‐pyrrolidino is markedly superior to either dimethylamino or 1‐piperidino) and the importance of the vinylic hydrogen atom (sharp falls in potency follow its replacement by methyl).

Endogenous histamine in the medial septum–diagonal band complex increases the release of acetylcholine from the hippocampus: a dual‐probe microdialysis study in the freely moving rat

“…Perfusion of MSA‐DB with 0.5 µ m triprolidine, an H 1 receptor antagonist (Ison & Casy, 1971), failed to alter ACh spontaneous release from the hippocampus during a 40‐min perfusion. The changes in hippocampal ACh release were always within the range of variability (± 15%) seen between individual 20‐min collection periods during MSA‐DB perfusion with control medium (data not shown).…”

“…Stimulation of transmitter release by H 2 receptor activation occurs in other brain regions, because H 2 receptor activation released endogenous noradrenaline from rat hypothalamic slices (Blandina et al ., 1989) and endogenous enkephalin from mouse striatum (Garbarg et al ., 1991). Conversely, modulation of ACh release from the hippocampus did not involve H 1 receptors because MSA‐DB perfusion with the H 1 antagonist triprolidine, at a concentration > 500 times its K d for the H 1 receptor (Ison & Casy, 1971), failed to modify both spontaneous and thioperamide‐evoked release of ACh.…”

Inhibition of cortical acetylcholine release and cognitive performance by histamine H3 receptor activation in rats

“…Conversely, neither 100 nM triprolidine, antagonist of the H, receptor (Ison et al, 1971), nor 100 pM cimetidine, an H2 receptor antagonist , prevented 100 gUM histamine-elicited inhibition of 100 mM K+-evoked ACh release (Figure 4). In the absence of histamine both failed to alter 100 mM K+-evoked ACh release.…”

“…Clobenpropit, a competitive antagonist at H3 receptors with reported pA2 values of 9.5 in mouse cortical slices (Kathmann et al, 1993) and 9.9 in guinea-pig ileum (Van der Goot et al, 1992), administered at nanomolar concentrations directly into the cortex, fully antagonizes the inhibition produced by 100 gM histamine. Confirmation of H3 receptor involvement stems also from observations that histamineinduced inhibition is resistant to antagonism by triprolidine and cimetidine at concentrations more than 400 times their Kd for the HI (Ison et al, 1971) and the H2 receptor, respectively. Furthermore, histamine receptor agonists TEA and dimaprit, at concentrations sufficient to activate fully HI (Ganellin, 1982) and H2 (Parson et al, 1977) (Clapham & Kilpatrick, 1992;Arrang et al, 1995) and the maximal inhibition, about 40%, was similar to that observed in this study.…”

Interactions between histaminergic and cholinergic systems in learning and memory

“…Oppositely, neither 2-thiazolylethylamine [45], an agonist showing some selectivity for H 1 receptors, nor the H 2 receptor agonist dimaprit [98] modified potassium-evoked release of ACh [14]. The inhibitory effect of 100 mM histamine, a concentration producing the maximal effect [14], was completely prevented by histamine H 3 receptor antagonists, such as clobenpropit [126] and thioperamide, but was resistant to antagonism by triprolidine [65] and cimetidine, antagonists at histamine H 1 and H 2 but not H 3 receptors [14,15]. All agonists and antagonists were administered locally, dissolved into the perfusion medium.…”