Structure-activity relationships of new 1-substitutedmethyl-4-[5-(N-methyl-N-propylamino)pentyloxy]piperidines and selected 1-[(N-substituted-N-methyl)-3-propyloxy]-5-(N-methy-l-N-propyl)-pentanediamines as H3 -antagonists.

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).

New 1-benzyl-4-hydroxypiperidine derivatives as non-imidazole histamine H3 receptor antagonists.

A series of 1-benzyl-4-(3-aminopropyloxy)piperidine and 1-benzyl-4-(5-aminopentyloxy)piperidine derivatives has been prepared. The 1-benzyl-4-hydroxypiperidine derivatives obtained were evaluated for their affinities at recombinant human histamine H(3 )receptor, stably expressed in HEK 293T cells. All compounds investigated show moderate to pronounced in-vitro affinities. The most potent antagonists in this series 9b2 (hH(3)R, pK(i) = 7.09), 9b1 (hH(3)R, pK(i) = 6.78), 9b5 (hH(3)R, pK(i) = 6.99), and 9b6 (hH(3)R, pK(i )= 6.97) were also tested in vitro as H(3 )receptor antagonists - the electrically evoked contraction of the guinea-pig jejunum. The histaminergic H(1) antagonism of selected compounds 9b1, 9b2, and 9b4-9b6 was established on the isolated guinea-pig ileum by conventional methods; the pA(2) values were compared with the potency of pyrilamine. The compounds did not show any H(1) antagonistic activity (pA(2) < 4; for pyrilamine pA(2) = 9.53).