Abstract:
:Novel, potent non-imidazole histamine H3 receptor antagonists have been prepared and in vitro tested as H3 -receptor antagonists (the electrically evoked contraction of the guinea-pig jejunum). The present compounds contain a 4-hydroxypiperidine core, which behaves as a conformationally restricted version of the 3-amino-1-propanol moiety common to the many previously described non-imidazole H3 ligands. Detailed structure-activity studies revealed that 1-(2-benzofuranylmethyl)- 5c (pA2 = 8.47 ± 0.05) and 1-(3-benzofuranylmethyl)-4-[5-(N-methyl-N-propyl)pentyloxy]piperidine 5d (pA2 = 8.15 ± 0.07) exhibit high potency for the H3 histamine receptor. In addition, the potency of selected 1-[(N-substituted-N-methyl)-3-propyloxy]-5-(N-methyl-N-propyl)pentanediamines as antagonist of the H3 histamine receptor was also evaluated. Replacement of the 4-hydroxypiperidine of the leads 7 and 5c by a highly flexible 3-(methylamino)propyloxy chain yields compounds 6a (pA2 = 8.02) and 6b (pA2 = 6.23) with higher and lower potency than their piperidine analogues (7, pA2 = 7.79; 5c, pA2 = 8.47), respectively. The histaminergic H1 antagonism of selected compounds 5c, 5d and 6a has been established on the isolated guinea-pig ileum by conventional methods; the pA2 values have compared with the potency of pyrilamine. None of them showed any H1 -antagonistic activity (pA2 < 4; for pyrilamine pA2 = 8.5).
journal_name
Chem Biol Drug Desjournal_title
Chemical biology & drug designauthors
Masłowska-Lipowicz I,Walczyński Kdoi
10.1111/cbdd.12206subject
Has Abstractpub_date
2014-01-01 00:00:00pages
106-18issue
1eissn
1747-0277issn
1747-0285journal_volume
83pub_type
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