title: 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.
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).
authors: Department of Synthesis and Technology of Drugs, Medical University, Muszyńskiego Street 1, 90-151, Łódź, Poland.
authors: Iwona
authors: I
authors: Masłowska-Lipowicz
authors: Krzysztof
authors: K
authors: Walczyński
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007583:Jejunum / Q000187:drug effects / Q000502:physiology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010880:Piperidines / Q000737:chemistry; D012372:ROC Curve; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D006633:Histamine Antagonists; D010880:Piperidines; D018100:Receptors, Histamine H3; C032727:piperidine
keywords: 1-[(N-substituted-N-methyl)-3-propyloxy]-5-(N-methyl-N-propyl)pentanediamines; 1-substitutedmethyl-4-[5-(N-methyl-N-propylamino)pentyloxy]piperidines; H3 non-imidazole antagonists; histamine H3-receptor