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PubMed1988

Synthesis and serotonin receptor affinities of a series of enantiomers of alpha-methyltryptamines: evidence for the binding conformation of tryptamines at serotonin 5-HT1B receptors.

A procedure for the preparation of optically pure alpha-methyltryptamines (AMTs) from substituted indoles was developed. The key step in the sequence was the reductive amination of substituted indole-2-propanones with the commercially available pure enantiomers of alpha-methylbenzylamine, followed by the chromatographic separation of the resulting pair of diastereomeric amines by preparative centrifugal (Chromatotron) chromatography. Catalytic N-debenzylation then afforded the pure AMT enantiomers. Optical purity was established by chiral HPLC analysis of the 2-naphthoylamide derivatives. An improved procedure for the preparation of indole-2-propanones was also developed. To probe structure-activity relationships of serotonin receptors, affinities of the alpha-methyltryptamine enantiomers were then measured at the 5-HT2 antagonist receptor subtype, with displacement of [3H]ketanserin, and were estimated at the 5-HT1B receptor, with displacement of [3H]serotonin, respectively, in rat frontal cortex homogenates. Enantioselectivity at the receptor subtypes varied, depending on aromatic substituents. For a 5-hydroxy or 5-methoxy, the S enantiomer had higher affinity or was equipotent to the R enantiomer. This selectivity at [3H]serotonin binding sites was reversed for 4-oxygenated alpha-methyltryptamines, where a 4-hydroxy or 4-methoxy did not enhance affinity over the unsubstituted compounds. These results can be explained, for the [3H]serotonin displacement data, if the binding conformation is one where the ethylamine side chain is trans and lying in a plane perpendicular to the indole ring plane.

Animals↗
PubMed1997

Inhibition of trigeminal neurones after intravenous administration of naratriptan through an action at 5-hydroxy-tryptamine (5-HT(1B/1D)) receptors.

1. The observation that 5-hydroxytryptamine (5-HT) is effective in treating acute attacks of migraine when administered intravenously resulted in a research effort that led to the discovery of the 5-HT(1B/1D) receptor agonist sumatriptan. 2. Clinical experience has shown sumatriptan to be an effective treatment with some limitations, such as relatively poor bioavailability, which naratriptan was developed to address. Increasing bioavailability has been achieved with greater lipophilicity and thus the potential for greater activity in the central nervous system. 3. In this study the increased access to central sites has been exploited in an attempt to characterize the pharmacology of those central receptors with the newer tools available. Trigeminovascular activation was examined in the model of superior sagittal sinus stimulation. 4. Cats were anaesthetized with alpha-chloralose (60 mg kg(-1), intraperitoneal), paralyzed (gallamine 6 mg kg(-1), intravenously) and ventilated. The superior sagittal sinus was accessed and isolated for electrical stimulation (250 micros pulses, 0.3 Hz, 100 V) by a mid-line circular craniotomy. The region of the dorsal surface of C2 spinal cord was exposed by a laminectomy and an electrode placed for recording evoked activity from sinus stimulation. 5. Stimulation of the superior sagittal sinus resulted in activation of cells in the dorsal horn of C2. Cells fired with a probability of 0.69+/-0.1 at a latency of 9.2+/-0.2 ms. Intravenous (i.v.) administration of naratriptan at clinically relevant doses (30 and 100 microg kg(-1)), inhibited neuronal activity in trigeminal neurones of the C2 dorsal horn, reducing probability of firing without affecting latency. 6. The effect of naratriptan could be reversed by administration of the selective 5-HT(1B/1D) receptor antagonist GR127935 (100 microg kg(-1), i.v.). 7. These data establish that naratriptan acts on central trigeminal neurones since sagittal sinus stimulation activates axons within the tentorial nerve and there are no inhibitory effects mediated within the trigeminal ganglion. Furthermore, given that this inhibition could be reversed by the relatively selective 5-HT(1B/1D) receptor antagonist GR127935, it is highly likely that the anti-migraine effects of drugs of this class with central nervous system access are mediated, at least in part, by 5-HT(1B/1D) receptors within the trigeminal nucleus.

Animals↗