Iodoaminopotentidine and related compounds: a new class of ligands with high affinity and selectivity for the histamine H2 receptor

Abstract

The synthesis and biological evaluation of a new class of histamine H2 antagonists with N-cyano-N'-[omega-[3-(1-piperidinylmethyl)phenoxy] alkyl]guanidine partial structure are described as part of an extensive research program to find model compounds for the development of new radioligands with high H2 affinity and specific activity. High receptor affinity is achieved by an additional (substituted) aromatic ring, which is connected with the third guanidine N by a carbon chain spacer and an amine, carboxamide, ester, or sulfonamide link ("polar group"). In functional studies for H2 antagonistic activity and other pharmacological actions [e.g. H1 antihistaminic, antimuscarinic, antiadrenergic (alpha 1, beta 1), 5-HT2 blocking activity] in the isolated guinea pig atrium and ileum and rat aorta and tail artery, the compounds proved to be highly potent and selective histamine H2 receptor antagonists. The H2 antagonistic activity is mainly depending on the length of both the N'-alkyl chain (chain A) and the N"-spacer (chain B). Compounds with a C3 chain A and a C2 chain B are most potent in the preferred group of substances, i.e., the carboxamide series. A wide variety of substituents at the aromatic ring is tolerated, among them iodine, amino, and azido groups. These compounds are up to 32 times more potent than cimetidine in the isolated guinea pig right atrium. The replacement of the carboxamide by an ester group (44c) is well tolerated, while replacement of the cyanoguanidine by an urea group results in nearly 100-fold decrease in activity (46c,e). The iodinated benzamides are among the most potent H2 antagonists known so far. The [125I]-labeled form of 31f ([125I]iodoaminopotentidine, [125I]-N-[2-(4-amino-3-iodobenzamido) ethyl]-N'-cyano-N"-[3-[3-(1-piperidinylmethyl) phenoxy]propyl]guanidine) and its photolabile analogue 31h ([125I]iodoazidopotentidine, [125I]-N-[2-(4-azido-3- iodobenzamido)ethyl]-N'-cyano-N"-[3-[3-(1-piperidinyl-methyl)pheno xy] propyl]guanidine) proved to be useful probes for reversible and irreversible labeling of the histamine H2 receptor. Radioligand binding studies in guinea pig cerebral membranes revealed considerably higher H2 receptor affinity for 31f (pKi = 9.15), 31h (pKi = 8.58), and some analogues than functional experiments (guinea pig atrium), presumably reflecting an easier access to the H2 receptors in membranes.

Cardiac and gastric effects of histamine H2 receptor antagonists: no evidence for a correlation between lipophilicity and receptor affinity

“…However, neither APT nor I-APT modified the acid secretion induced by forskolin (which acts at intracellular sites beyond the H2 receptor) and the inotropic response to adrenaline in the papillary muscle, indicating that both compounds are selective for H2 receptors at concentrations that depressed the maximal response to histamine. Indeed, other studies have previously shown that these compounds are highly selective for H2 receptors and ['251l-APT has been considered the most valuable probe for labelling H2 receptors in different tissues (Ruat et al, 1990;Hirschfeld et al, 1992). Receptor-protection experiments in the present study showed that the co-administration of the surmountable antagonist ranitidine was capable of restoring the maximal response to histamine after APT, suggesting that APT and ranitidine interact with a common binding site.…”

“…Those compounds with more lipophilic structural components expressed significantly lower pD2 values in the papillary muscle (Buschauer, 1989). Radioligand binding studies in guinea-pig cerebral membranes revealed that APT and I-APT have high affinity for H2 receptors (pK =8.01 and 9.15, respectively), being significantly more potent in binding assays than in functional experiments (guinea-pig atrium); this presumably reflects an easier access of these compounds to the H2 receptors in membrane preparations rather than an H2 receptor heterogeneity (Hirschfeld et al, 1992). Several different mechanisms can account for the insurmountable antagonism produced by APT and I-APT in heart and stomach: non-specific effects involving sites other than H2 receptors, allosteric interaction, irreversible or slowly reversible antagonism.…”

“…A different number of spare receptors could also explain why APT and I-APT did not produce insurmountable antagonism in the right atrium (Hirschfeld et al, 1992); in this tissue, in fact, a receptor reserve of approximately 97% at maximal histamine responses has been calculated (Kramer et al, 1987).…”

Mutations of Cys-17 and Ala-271 in the Human Histamine H2Receptor Determine the Species Selectivity of Guanidine-Type Agonists and Increase Constitutive Activity

“…ARP and BU-E-43 were synthesized as described previously (Buschauer, 1989). APT and IAPT were prepared as described previously (Hirschfeld et al, 1992). Suprahistaprodifen was synthesized as described previously (Elz et al, 2000).…”

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…In the rat, Northern hybridization analysis has revealed high expression in various parts of the brain, including cerebral cortex, striatum, hippocampus, and hypothalamus. The highest mRNA expression in the rat brain was seen in brain stem Hirschfeld et al, 1992), where several other methods have suggested important physiologic actions. In another quantitative study, the expression in the stomach was reported to be 10-fold higher than that of several brain regions .…”