Propranolol glycol is a major metabolite of propranolol in man with potent anticonvulsant activity. Propranolol glycol appears to be more potent for this effect than propranolol. The onset of action of propranolol glycol is instantaneous but delayed for propranolol. Maximal anticonvulsant activity for propranolol glycol is obtained immediately and for propranolol 10 minutes after administration. The delayed onset of this action of propranolol and the immediate anticonvulsant activity of propranolol glycol strongly suggest that the anticonvulsant properties of propranolol may be related to its conversion to propranolol glycol. Propranolol and propramioiol glycol have a similar spectrum of gross behavioral effects ranging from quietness at low doses to paralysis at high doses. These observations suggest the possibility that propranolol glycol may be contributing to some of the therapeutically significant effects of propranolol in the central nervous system.

N-MPPP HYDROCHLORIDE is high-affinity κ agonist with no measured binding at μ or δ sites.

S-fluoxetine is an enantiomer of fluoxetine, a potent and selective inhibitor of the neuronal serotonin-uptake carrier and a clinically effective antidepressant. R-fluoxetine and S-fluoxetine enantiomers are nearly equipotent at blocking serotonin reuptake. In all biochemical and pharmacological studies, the eudismic ratio for the fluoxetine enantiomers is also near unity. A study examining the relative contributions of CYP enzymes to the metabolism of S-fluoxetine, and R-fluoxetine found dramatic differences. These data led to discovery programs between Lilly and Sepracor for the individual enantiomers. S-fluoxetine was studied in a phase 2 clinical trial for the prophylaxis of migraine, however, development was discontinued.

Senkyunolide I is an active ingredient of Rhizoma Chuanxiong, a Chinese medicinal herb commonly used for the treatment of cardiovascular ailments. Senkyunolide I is presentative metabolite of ligustilide in vivo and in vitro, is one of the most important bioactive constituents of chuanxiong. It was fount, that it could treat migraines, although the mechanism is unclear.

(S)-AM-1241 is enantiomer of the CB2 modulator, that has most penetrated the literature, has proven an important research tool for investigating CB2-mediated antinociception. (R, S)-AM1241 produces antinociception following local and systemic administration in naive rats. Behavioral, neurochemical, and electrophysiological studies suggest that (R, S)-AM1241 suppresses persistent pain through a CB2-specific mechanism. In cAMP inhibition assays, (R, S)-AM1241 was found to be an agonist at human CB(2), but an inverse agonist in rat and mouse CB(2) receptors. (R)-AM1241 bound with more than 40-fold higher affinity than (S)-AM1241, to all three CB(2) receptors and displayed a functional profile similar to that of the racemate. In contrast, S-AM1241 was an agonist at all three CB(2) receptors. In pain models, S-AM1241 was more efficacious than either R-AM1241 or the racemate. In preclinical studies (R, S)-AM1241, (R)-AM1241, and (S)-AM1241 produced antinociception to thermal, but not mechanical, stimulation of the hind paw in naive rats. Antinociception produced by (R, S)-AM1241 and (S)-AM1241 exhibited an inverted U-shaped dose-response curve. (R)-AM1241 produced greater antinociception than either (S)-AM1241 or (R, S)-AM1241. (R, S)-AM1241, (R)-AM1241, and (S)-AM1241 each produced CB2-mediated antinociception that was blocked by SR144528 but not by rimonabant. Local and systemic naloxone blocked morphine-induced antinociception but did not block antinociceptive effects of (R, S)-AM1241, (R)-AM1241, or (S)-AM1241. The physiological and toxicological properties of (S)-AM-1241 have not been evaluated in humans.

LY344864 is a selective 5-HT1F receptor agonist (EC50 = 3 nM). In a rat model of migraine, LY344864 inhibited neurogenic dural inflammation following i.v. and oral administration.

(R)-AM-1241 is enantiomer of the CB2 modulator, that has most penetrated the literature, has proven an important research tool for investigating CB2-mediated antinociception. (R, S)-AM1241 produces antinociception following local and systemic administration in naive rats. Behavioral, neurochemical, and electrophysiological studies suggest that (R, S)-AM1241 suppresses persistent pain through a CB2-specific mechanism. In cAMP inhibition assays, (R, S)-AM1241 was found to be an agonist at human CB(2), but an inverse agonist in rat and mouse CB(2) receptors. (R)-AM1241 bound with more than 40-fold higher affinity than (S)-AM1241, to all three CB(2) receptors and displayed a functional profile similar to that of the racemate. In contrast, S-AM1241 was an agonist at all three CB(2) receptors. In pain models, S-AM1241 was more efficacious than either R-AM1241 or the racemate. In preclinical studies (R, S)-AM1241, (R)-AM1241, and (S)-AM1241 produced antinociception to thermal, but not mechanical, stimulation of the hind paw in naive rats. Antinociception produced by (R, S)-AM1241 and (S)-AM1241 exhibited an inverted U-shaped dose-response curve. (R)-AM1241 produced greater antinociception than either (S)-AM1241 or (R, S)-AM1241. (R, S)-AM1241, (R)-AM1241, and (S)-AM1241 each produced CB2-mediated antinociception that was blocked by SR144528 but not by rimonabant. Local and systemic naloxone blocked morphine-induced antinociception but did not block antinociceptive effects of (R, S)-AM1241, (R)-AM1241, or (S)-AM1241. The physiological and toxicological properties of (R)-AM-1241 have not been evaluated in humans.

AM-1241, was developed at the University of Connecticut. AM-1241 was derived from the known non-selective indole class of cannabinoid receptor agonists represented by WIN55212-2 and JWH-015. Compared to earlier agonists that exhibited modest selectivities, AM-1241 exhibited 82-fold selectivity for CB2 over CB1 based on binding affinity assays. Using AM-1241, it was demonstrated that a selective CB2 receptor agonist provides relief of pain without the psychotropic effects produced by a pan-cannabinoid receptor agonist. After injection of AM-1241 into the hindpaw of a mouse, analgesic activity toward a thermal stimulus applied to the same paw was observed. Co-administration of a CB2 receptor antagonist blocked the effect, while a CB1 antagonist did not. The results of this initial study led researchers to investigate the use of a CB2 receptor selective agonist for the treatment of pain as well as other disease states that involve the CB2 receptor. It was found that AM-1241 inhibited nociception in CB+/+ mice, but not CB2+/+ littermates, providing strong evidence of its direct activation of CB2. AM-1241 was shown to dose-dependently inhibit capsaicin-induced release of the pain biomarker calcitonin gene-related peptide (CGRP) in rat spinal cord slices, a result that also suggests the presence of CB2 in neurons of the spinal cord. AM-1241 has being shown to be a promising target for the management of cancer pain.

5-carboxamidotryptamine (5-CT) is a 5-HT1 agonist with high affinity at 5-HT1A, 5-HT1B, 5-HT1D, 5-HT5 and 5-HT7 receptors. As one of the first compounds reported active at 5-HT1B, 5-carboxamidotryptamine was originally investigated as a potential treatment for migraine. During preclinical studies, 5-CT was found to cause vasodilatation of carotid circulation and hypotension in animals, effects that were later attributed to potent agonist activity at 5-HT7. Subsequent structural modifications of 5-CT led to the discovery of the anti-migraine drug sumatriptan. 5-CT is primarily used as a pharmacological tool for study of 5-HT1 and 5-HT7 mediated functional responses.

Betonicine (trans-2-carboxy-4-hydroxy-1,1,-dimethylpyrrolidinium hydroxide, inner salt) and its cis isomer, turicine, are naturally occurring substituted pyrrolidines. Betonicine was used as an analgesic 1000 years ago and is still available commercially from herbalists today. Betonicine has been isolated from Achillea millefolium L. (Compositae) and probably from A. atrata L. (Compositae); it is an alkaloid. Proline betaine and Betonicine were identified as metabolically inert cell protectants against extremes in osmolarity and growth temperatures.