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

Article abstract of DOI:10.1021/jm00090a013

The synthesis and biological evaluation of a new class of histamine H₂ antagonists with N-cyano-N'-[ω-[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 (α₁, β₁), 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 ([¹²⁵]iodoaminopotendine, [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)phenoxy]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 (pK(i) = 9.15), 31h (pK(i) = 8.58), and some analogues than functional experiments (guinea pig atrium), presumably reflecting an easier access to the H₂ receptors in membranes.