Differentiation between Partial Agonists and Neutral 5-HT_1BAntagonists by Chemical Modulation of 3-[3-(N,N-Dimethylamino)propyl]-4-hydroxy-N-[4-(pyridin-4-yl)phenyl]benzamide (GR-55562)

Abstract

The synthesis and binding affinity at cloned h5-HT1D, h5-HT1D, and h5-HT1A receptors of 3-[3-(N,N-dimethylamino)propyl]-4-hydroxy- N-[4-(pyridin-4-yl)phenyl]benzamide (2, GR-55562) and four O-methylated analogs are described. The functional activity of these compounds was determined at the h5-HT1B receptor using a [35S]GTP gamma S binding assay. The four analogs have been prepared in order to evaluate the influence of the alkylamino side chain conformation on binding and intrinsic activity. Whereas 2 and its derivatives display a similar binding affinity profile, major differences arise from analysis of the intrinsic activity data at h5-HT1B receptors. The O-methylated analog of 2, 3-[3-(N,N-dimethylamino)propyl]-4-methoxy- N-[4-(pyridin-4-yl)phenyl]benzamide (3a), and the (1Z)-3-(N,N-dimethylamino)prop-1-enyl derivative (3c) act as neutral and potent antagonists (in a similar way to 2), while the 3-(N,N-dimethylamino)-prop-1-ynyl (3b) and (1E)-3-(N,N-dimethylamino)prop-1-enyl (3d) analogs display nonnegligible agonist activity. Molecular modeling studies show that, when the common triaryl portions of the molecules are overlapped, the partial agonists and the neutral antagonists differ by a near-orthogonal orientation of the NH+ projection to the hydrogen-bond receptor site.

Pharmacological characterization of 5‐HT1B receptor‐mediated inhibition of local excitatory synaptic transmission in the CA1 region of rat hippocampus

“…GR 55562, a selective 5‐HT 1B antagonist (Walsh et al ., 1995; Lamothe et al ., 1997), completely antagonised the actions of CP 93129 and 5‐CT on poly‐epscs. The GR 55562 antagonism appeared competitive and the calculated K B values (104–171 n M for CP 93129 and 72–152 for 5‐CT) are fairly well in agreement with those described in binding studies (39–54 n M ; Lamothe et al ., 1997; Pauwels et al ., 1999). Moreover, the K B values obtained using either CP 93129 or 5‐CT as agonists were virtually the same.…”

“…In addition to 8‐OH‐DPAT, to investigate the possibility of the involvement of an atypical 5‐HT 1A receptor, we used a wider range of 5‐HT receptor ligands, including rodent 5‐HT 1B receptor selective agonist CP 93129 (Macor et al ., 1990) or antagonists such as CR 55562 (Walsh et al ., 1995; Lamothe et al ., 1997) and cyanopindolol (Maura et al ., 1987; Hoyer et al ., 1994).…”

Biphasic alterations in Serotonin‐1B (5‐HT1B) receptor function during abstinence from extended cocaine self‐administration

“…Following collection of 6 baseline samples, the dialysate perfusate was switched to an aCSF solution containing 30 µ m CP 93, 129 for 30 min, followed by 60 min washout with drug‐free aCSF, a second 30 min perfusion with an aCSF containing 100 µ m CP 93, 129 and an additional 40 min washout with drug‐free aCSF. A second experiment was conducted in cocaine‐naïve subjects ( n = 5) to evaluate the ability of the selective 5‐HT 1B antagonist GR 55562 (Lamothe et al . 1997) to block the effect produced by perfusate CP 93, 129.…”

“…The doses of 5‐HT 1B compounds were chosen based on the reported affinity of these compounds for 5‐HT 1B receptors (Macor et al . 1990; Lamothe et al . 1997) and on previous reports that have observed significant 5‐HT 1B receptor‐mediated neurochemical effects of these compounds when delivered locally by reverse dialysis (Yan and Yan 2001a; O'Dell and Parsons 2004).…”

Effect of different 5‐hydroxytryptamine receptor subtype antagonists on the micturition reflex in rats

“…The affinity of the compounds tested for the human recombinant 5‐HT 1A receptors, and their effects on [ 35 S]guanosine 5′‐(γ‐thio)triphosphate (GTPγS) binding in HeLa cells (a functional model of receptor‐mediated G‐protein activation) were also evaluated. The following antagonists were evaluated: 4‐(2′‐methoxy‐phenyl)‐1‐[2′‐(n‐2′′‐pyridinyl)‐p‐iodobenzamido]‐ethyl‐piperazine (p‐MPPI, 5‐HT 1A selective [10]), GR 55562 (5‐HT 1B selective [11]), ketanserin (5‐HT 2A partially selective [12]), SB 242084 (5‐HT 2C selective [13]), mesulergine (5‐HT 2 nonselective [12]), Y 25130 and zatosetron (5‐HT 3 selective [14,15]), RS 39604 (5‐HT 4 selective [16]), Ro 04–6790 (5‐HT 6 selective [17]), and methiothepin, a compound showing high affinity for most of 5‐HT subfamilies, including 5‐HT 2A,6,7 [18]. Some of the present data are published in abstract form [19].…”