RESUMEN
A series of rotationally restricted phenolic analogs of the neurotransmitter serotonin has been synthesized with the 5-hydroxyindole portion of serotonin replaced by a dihydropyrano[3,2-e]-indole (1, 3, 4, and 5) and a dihydropyrano[2,3-f]indole (2). The receptor binding profile of these compounds has been studied and compared to the natural substrate serotonin. The dihydropyrano[3,2-e]indole derivatives (1, 3, 4, and 5) possess lower affinity for 5-HT1 receptors but equal or greater affinity for 5-HT2 receptors. Like serotonin, these compounds dose-dependently stimulated phosphatidylinositol turnover in rat brain slices. Moreover, the response to 1-(2-aminoethyl)-3-methyl-8,9-dihydropyrano[3,2-]indole (5, CP-132,484) and 1-(2-aminoethyl)-8,9-dihydropyrano[3,2-e]indole (4) is selectively antagonized by 5-HT2 receptor antagonists establishing these tryptamines as selective 5-HT2 receptor agonists. The high affinity and potency of 5 for 5-HT2 receptors suggests that the C5-hydroxy group in serotonin can function as a hydrogen bond acceptor in a 5-HT2 receptor with a directionality of interaction which is down and away from C6 in serotonin (Figure 5). Furthermore, the potent affinity of these compounds for 5-HT2 receptors coupled with their poor affinity for 5-HT1 receptors indicates that the aminoethyl side chain of serotonin adopts significantly different conformations in 5-HT1 versus 5-HT2 receptors.
Asunto(s)
Indoles/síntesis química , Agonistas de Receptores de Serotonina/síntesis química , Serotonina/análogos & derivados , Animales , Indoles/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Ratas , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
Ifenprodil (1) represents a new class of N-methyl-D-aspartate (NMDA) antagonist. This drug also possesses potent activity at several other brain receptors (most notably alpha 1 adrenergic receptors). We have prepared the enantiomers and diastereomers of ifenprodil along with a series of partial structures in order to explore the basic structure activity relations within this class of compounds. From this study, it is clear that alpha 1 adrenergic and NMDA receptor activities may be separated by selection of the threo relative stereochemistry. Examination of the optical isomers of threo-ifenprodil (2) reveals that no further improvement in receptor selectivity is gained from either antipode. Individual removal of most of the structural fragments from the ifenprodil molecule generally results in less active compounds although fluorinated derivative 9 with threo relative stereochemistry is somewhat more potent and substantially more selective for the NMDA receptor. Finally a minimum structure for activity in this series (14) has been identified. This stripped-down version of ifenprodil possesses nearly equivalent affinity for the NMDA receptor with no selectivity over alpha 1 adrenergic receptors.
Asunto(s)
Antagonistas Adrenérgicos alfa/farmacología , N-Metilaspartato/antagonistas & inhibidores , Piperidinas/química , Antagonistas Adrenérgicos alfa/química , Animales , Estructura Molecular , Piperidinas/metabolismo , Piperidinas/farmacología , Ratas , Receptores Adrenérgicos alfa/efectos de los fármacos , Receptores Adrenérgicos alfa/metabolismo , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (20, CP-101,606) has been identified as a potent and selective N-methyl-D-aspartate (NMDA) antagonist through a structure activity relation (SAR) program based on ifenprodil, a known antihypertensive agent with NMDA antagonist activity. Sites on the threo-ifenprodil skeleton explored in this report include the pendent methyl group (H, methyl, and ethyl nearly equipotent; propyl much weaker), the spacer group connecting the C-4 phenyl group to the piperidine ring (an alternating potency pattern with 0 and 2 carbon atoms yielding the greatest potency), and simple phenyl substitution (little effect). While potent NMDA antagonists were obtained with a two atom spacer, this arrangement also increased alpha 1 adrenergic affinity. Introduction of a hydroxyl group into the C-4 position on these piperidine ring resulted in substantial reduction in alpha 1 adrenergic affinity. The combination of these observations was instrumental in the discovery of 20. This compound potently protects cultured hippocampal neurons from glutamate toxicity (IC50 = 10 nM) while possessing little of the undesired alpha 1 adrenergic affinity (IC50 approximately 20 microM) of ifenprodil. Furthermore, 20 appears to lack the psychomotor stimulant effects of nonselective competitive and channel-blocking NMDA antagonists. Thus, 20 shows great promise as a neuroprotective agent and may lack the side effects of compounds currently in clinical trials.
Asunto(s)
N-Metilaspartato/antagonistas & inhibidores , Degeneración Nerviosa/efectos de los fármacos , Piperidinas/farmacología , Animales , Muerte Celular/efectos de los fármacos , Células Cultivadas , Genes fos/efectos de los fármacos , Hipocampo/citología , Hipocampo/efectos de los fármacos , Masculino , Ratones , N-Metilaspartato/farmacología , Piperidinas/síntesis química , Piperidinas/química , Ratas , Relación Estructura-ActividadAsunto(s)
Indoles/síntesis química , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/síntesis química , Indoles/metabolismo , Indoles/farmacología , Conformación Molecular , Estructura Molecular , Agonistas de Receptores de Serotonina/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Sumatriptán/metabolismo , Sumatriptán/farmacologíaAsunto(s)
Indoles/síntesis química , Pirrolidinas/síntesis química , Agonistas de Receptores de Serotonina/síntesis química , Indoles/farmacología , Pirrolidinas/farmacología , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacología , EstereoisomerismoRESUMEN
3-(1,2,5,6-Tetrahydro-4-pyridyl)-5-n-propoxyindole (CP-96,501) was found to be more selective ligand at the serotonin 5-HT1B receptor than the commonly used 5-HT1B agonist, 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-methoxyindole (RU 24969). In rat brain membranes, the tritiated derivative, [3H]CP-96,501, was found to bind with a high affinity (KD, 0.21 nM) to a single binding site (nH, 1.0). The receptor density of this site (Bmax, 72 fmol/mg of protein) matched that of the 5-HT1B receptor determined with [3H]5-HT. Competition curves of 16 serotonergic compounds in [3H]CP-96,501 binding also indicated a single binding site. The rank order of their binding affinities with this new radioligand showed a high degree of correlation with their affinities at the 5-HT1B receptor determined with [3H]5-HT or [125I]iodocyanopindolol. Serotonergic compounds displayed competitive inhibition of [3H]CP-96,501 binding. In the presence of 5'-guanylylimidodiphosphate [Gpp(NH)p], [3H]CP-96,501 to displace [125I]iodocyanopindolol binding was also decreased. These findings are consistent with the agonist nature of CP-96,501. The results of this study suggest that [3H]CP-96,501 is a useful agonist radioligand for the 5-HT1B receptor.