251907-48-9Relevant academic research and scientific papers
Structure-activity relationships at the monoamine transporters and σ receptors for a novel series of 9-[3-(cis-3,5-dimethyl-1- piperazinyl)propyl]carbazole (rimcazole) analogues
Husbands, Stephen M.,Izenwasser, Sari,Kopajtic, Theresa,Bowen, Wayne D.,Vilner, Bertold J.,Katz, Jonathan L.,Newman, Amy Hauck
, p. 4446 - 4455 (2007/10/03)
9-[3-(cis-3,5-Dimethyl-1-piperazinyl)propyl]carbazole (rimcazole) has been characterized as a receptor antagonist that binds to the dopamine transporter with moderate affinity (K(i) = 224 nM). Although the binding affinities at the dopamine transporter of rimcazole and cocaine are comparable, rimcazole only depressed locomotor activity in mice and antagonized the stimulant effects produced by cocaine. The neurochemical mechanisms underlying the attenuation of cocaine's effects are not understood, although interaction at a low affinity site/state of the dopamine transporter has been suggested. To explore further this class of compounds, a series of rimcazole analogues was designed and synthesized. Displacement of [3H]WIN 35,428 binding at the dopamine transporter in rat caudate-putamen revealed that aromatic substitutions on rimcazole were not well tolerated, generally, with significant reductions in affinity for the 3,6-dibromo (5; K(i) = 3890 nM), 1,3,6-tribromo (6; K(i) = 30300 nM), 3-amino (8; K(i) = 2400 nM), and 3,6-dinitro (9; K(i) = 174000 nM) analogues. The N-phenylpropyl group was the only terminal piperazine nitrogen substituent that retained moderate affinity at the dopamine transporter (11; K(i) = 263 nM). Analogues in which the carbazole ring was replaced with a freely rotating diphenylamine moiety were also prepared. Although the diphenylamino analogue in which the terminal piperazine nitrogen was unsubstituted, as in rimcazole, demonstrated relatively low binding affinity at the dopamine transporter (24; K(i) = 813 nM), the N-phenylpropyl analogue was found to have the highest affinity for the dopamine transporter within the series (25; K(i) = 61.0 nM). All of the analogues that had affinity for the dopamine transporter inhibited [3H]dopamine uptake in synaptosomes, and potencies for these two effects showed a positive correlation (r2 = 0.7731, p = 0.0018). Several of the analogues displaced [3H]paroxetine from serotonin transporters with moderate to high affinity, with the N-phenylpropyl derivative (11) having the highest affinity (K(i) = 44.5 nM). In contrast, none of the analogues recognized the norepinephrine transporter with an affinity of 1 and σ2 receptors were also determined, and several of the compounds were more potent than rimcazole with affinities ranging from 97 nM to >6 μM at σ1 sites and 145 to 1990 nM at σ2 sites. The compound with the highest affinity (25) at σ1 sites was also the compound with highest affinity at the dopamine transporter. These novel rimcazole analogues may provide important tools with which to characterize the relationship between the low affinity site or state of the dopamine transporter, σ receptors, and their potential roles in modulating cocaine's psychostimulant actions.
Synthesis of novel GABA uptake inhibitors. 4. Bioisosteric transformation and successive optimization of known GABA uptake inhibitors leading to a series of potent anticonvulsant drug candidates
Andersen, Knud Erik,S?rensen, Jan L.,Huusfeldt, Per O.,Knutsen, Lars J. S.,Lau, Jesper,Lundt, Behrend F.,Petersen, Hans,Suzdak, Peter D.,Swedberg, Michael D. B.
, p. 4281 - 4291 (2007/10/03)
By bioisosteric transformations and successive optimization of known GABA uptake inhibitors, several series of novel GABA uptake inhibitors have been prepared by different synthetic approaches. These compounds are derivatives of nipecotic acid and guvacine, substituted at the nitrogen of these amino acids by various lipophilic moieties such as diarylaminoalkoxyalkyl or diarylalkoxyalkyl. The in vitro values for inhibition of [3H]GABA uptake in rat synaptosomes was determined for each compound, and it was found that the most potent compound from this series, (R)-1-(2-(3,3-diphenyl-1-propyloxy)ethyl)-3-piperidinecarboxylic acid hydrochloride (29), is so far the most potent parent compound inhibiting GABA uptake into synaptosomes. Structure-activity results confirm our earlier observations, that an electronegative center in the chain connecting the amino acid and diaryl moiety is very critical in order to obtain high in vitro potency. Several of the novel compounds were also evaluated for their ability in vivo to inhibit clonic seizures induced by a 15 mg/kg (ip) dose of methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM). Some of the compounds tested show a high in vivo potency comparable with that of the recently launched anticonvulsant product 6 ((R)-1-(4,4-bis(3-methyl-2- thienyl)-3-butenyl)-3-piperidinecarboxylic acid).
