The Bivalent Ligand Approach Leads to Highly Potent and Selective Acylguanidine-Type Histamine H₂ Receptor Agonists

Abstract

Bivalent histamine H(2) receptor (H(2)R) agonists were synthesized by connecting pharmacophoric 3-(2-amino-4-methylthiazol-5-yl)-, 3-(2-aminothiazol-5-yl)-, 3-(imidazol-4-yl)-, or 3-(1,2,4-triazol-5-yl)propylguanidine moieties by N(G)-acylation with alkanedioic acids of various chain lengths. The compounds were investigated for H(2)R agonism in GTPase and [(35)S]GTPγS binding assays at guinea pig (gp) and human (h) H(2)R-Gsα(S) fusion proteins including various H(2)R mutants, at the isolated gp right atrium, and in GTPase assays for activity on recombinant H(1), H(3), and H(4) receptors. The bivalent ligands are H(2)R partial or full agonists, up to 2 orders of magnitude more potent than monovalent acylguanidines and, with octanedioyl or decanedioyl spacers, up to 4000 times more potent than histamine at the gpH(2)R. In contrast to their imidazole analogues, the aminothiazoles are highly selective for H(2)R vs other HR subtypes. Compounds with (theoretically) sufficient spacer length (20 CH(2) groups) to simultaneously occupy two orthosteric binding sites in H(2)R dimers are nearly inactive, whereas the highest potency resides in compounds with considerably shorter spacers. Thus, there is no evidence for interaction with H(2)R dimers. The high agonistic potency may result from interaction with an accessory binding site at the same receptor protomer.

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

“…Very recently, the acylguanidine motif was incorporated into bivalent ligands for the H 2 receptor, resulting in the most potent H 2 receptor agonists reported so far (Birnkammer et al, 2012). Searching for potential pharmacological tools to study hypothetical H 2 receptor dimers (Fukushima et al, 1997), two hetarylpropylguanidine moieties were connected by alkanedioyl residues varying in chain lengths (spacer lengths between 6 and 27 Å were covered).…”

“…The data from the guinea pig H 2 receptor (GTPase assay, GTPgS binding assay) were largely consistent with the results from the isolated guinea pig right atrium. For instance, compounds with a decanedioyl spacer (UR-AK381, UR-AK480, UR-BIT82) were (nearly) full agonists and achieved up to 4000 times the potency of histamine at recombinant human and guinea pig H 2 receptor (Sf9 cell membranes), respectively (Birnkammer et al, 2012) (Fig. 9; Table 1).…”

[3H]UR‐DE257: Development of a Tritium‐Labeled Squaramide‐Type Selective Histamine H2 Receptor Antagonist

“…The K d value determined from saturation binding was applied for the calculation of K i values by means of the Cheng-Prusoff equation. [45] As summarized in Table 5, the hH 2 R binding affinity of the agonists histamine (K i = 534 nm), amthamine (K i = 244 nm), URBit24 [46] (K i = 7.1 nm) and UR-AK480 [47] (K i = 1.9 nm), and of the antagonists famotidine (K i = 136 nm), ranitidine (K i = 1730 nm), BMY 25368 (K i = 19 nm) and iodoaminopotentidine (K i = 0.31 nm) were consistent with reported data from functional and binding experiments. [40,48] The K i value of 24 a on the hH 2 R (28 nm), determined by competition binding experiments with the labeled analogue 24 b, corresponds very well to the K d value of compound 24 b (31 nm), and the data for the rat and guinea H 2 R species orthologues were in the same range (K i values: 16 and 43 nm, respectively).…”

“…[52,53]) expressing the hH 2 R-G saS or the gpH 2 R-G saS and on the isolated spontaneously beating guinea pig right atrium [46,54] were performed as previously described, except that the incubation period of the guinea pig atrium in the presence of the antagonists was extended to 60 min. Binding data on recombinant histamine receptor subtypes and orthologues expressed in Sf9 cells (hH 1 R + RGS4; hH 2 R-G saS , gpH 2 R-G saS , rH 2 R-G saS ; hH 3 R + G ia2 + b 1 g 2 ; hH 4 R + G ia2 + b 1 g 2 ) or HEK293T CRE-Luc cells [55] (hH 2 R) using the following radioligands: H 1 R,[ …”

Design and synthesis of new homo and hetero bis-piperazinyl-1-propanone derivatives as 5-HT7R selective ligands over 5-HT1AR

“…There are several papers describing the "bivalent ligand" approach, which have performed good results in terms of affinity and selectivity, [18][19][20][21] and to the best of our knowledge, in the field of the 5-HT 7 /5-HT 1A receptor ligands it was used only once before. 22 Given the importance of the 1-arylpiperazine moiety for its affinity to serotoninergic receptors, we have duplicated this template in order to identify homo and hetero bis-piperazine 5-HT 7 R selective ligands.…”