D-alanine piperazine-amides: novel non-imidazole antagonists of the histamine H 3 receptor

Detection of multiple H3 receptor affinity states utilizing [3H]A‐349821, a novel, selective, non‐imidazole histamine H3 receptor inverse agonist radioligand

“…The imidazoles thioperamide and clobenpropit displaced [ 3 H]A‐349821 to the same level as the non‐imidazole, A‐317920 (Figure 5d–f). In addition, a large panel of Abbott compounds from these three chemical series (previously described as H 3 receptor antagonists/inverse agonists), which displayed a wide range of potencies in the displacement of [ 3 H]N α MH binding (Faghih et al ., 2002, 2003a, 2003b; Turner et al ., 2003), were tested in competition with [ 3 H]A‐349821. For these compounds as well, competition curves displayed Hill slopes close to or slightly above unity and were best described by the one‐site analysis (Table 4).…”

“…Ciproxifan, proxyfan, and GT‐2331 ((1 S , 2 S )‐(+)‐4‐[2‐(5,5‐dimethyl‐hex‐1‐ynyl)‐cyclopropyl]‐1 H ‐imidazole) (Liu et al ., 2004) were synthesized at Abbott Laboratories. Nonlabelled A‐349821 ({4′‐[3‐(2 R ,5 R ‐dimethyl‐pyrrolidin‐1‐yl)‐propoxy]‐biphenyl‐4‐yl}‐morpholin‐4‐yl‐methanone) and other A‐compounds were prepared at Abbott laboratories as described previously (Faghih et al ., 2002, 2003a, 2003b; Turner et al ., 2003). Radiolabelled [ 3 H]N α MH was purchased from Perkin‐Elmer Life Sciences (Boston, MA, U.S.A.).…”

D‐Amino Acid Homopiperazine Amides: Discovery of A‐320436, a Potent and Selective Non‐Imidazole Histamine H3‐Receptor Antagonist

“…Additionally, we have previously reported on the propensity of D-amino acid motifs and their N-furanoyl analogues to enhance rH 3 and hH 3 -receptor binding potency, respectively, in a series of aminoalkoxycyclopropylketones [17,18]. However, these compounds lacked adequate hH 3 -receptor affinities (A-317920, Table 1).…”