ChemInform Abstract: STRUCTURE‐ACTIVITY RELATIONSHIPS IN PSYCHOTOMIMETIC PHENYLALKYLAMINES

Aldous, F. A. B.; Brewster, L.; Barrass, B. C.; Buxton, D. A.; Green, D. M.; Pinder, Ruth; Skeels, M.; Rich, P.; Tutt, K. J.

doi:10.1002/chin.197505187

Cited by 10 publications

(14 citation statements)

References 1 publication

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“…This lack of response suggests that S-DOI lacks the requisite efficacy at the 5-HT 2 receptor or is selectively metabolized. A stereoselective pharmacologic response has been reported for some 1-phenyl-2-aminopropane enantiomeric pairs in other in vivo studies (Shulgin, 1973;Aldous et al, 1974;Shulgin and Shulgin, 1991). This effect has been suggested to arise from the selective metabolism of the less active enantiomer.…”

mentioning

confidence: 54%

Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT_1A and 5-HT₂ Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys

May¹,

McLaughlin²,

Sharif³

et al. 2003

J Pharmacol Exp Ther

106

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Published investigations of serotonin-1A (5-hydroxytryptamine 1A ; 5-HT 1A ) receptor agonists and serotonin-2A (5-hydroxytryptamine 2A ; 5-HT 2A ) receptor antagonists in nonprimate species provide conflicting results with regard to their intraocular pressurelowering efficacy. Thus, their therapeutic utility in the treatment of human glaucoma has been confusing. We evaluated the effect of selected 5-HT 1A agonists and 5-HT 2A receptor antagonists on intraocular pressure in a nonhuman primate model, the conscious cynomolgus monkey with laser-induced ocular hypertension. Neither selective 5-HT 1A agonists [e.g., R-8-hydroxy-2-(di-n-propylamino)tetralin and flesinoxan] nor selective 5-HT 2 receptor antagonists [e.g.,pressure in the primate model following topical ocular administration. However, compounds that function as agonists at both the 5-HT 1A and 5-HT 2 receptors were found to effectively lower intraocular pressure in the model: 5-hydroxy-␣-methyltryptamine, 5-methoxy-␣-methyltryptamine, 5-hydroxy-N,N-dimethyltryptamine (bufotenine), and 5-methoxy-N,N-dimethyltryptamine. Furthermore, the selective 5-HT 2 receptor agonist R-(Ϫ)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane lowered intraocular pressure in the primate model, demonstrating a pharmacological response associated with activation of the 5-HT 2 receptor. These observations suggest that compounds that function as efficient agonists at 5-HT 2 receptors should be considered as potential agents for the control of intraocular pressure in the treatment of ocular hypertension and glaucoma in humans.Identification of several of the numerous serotonin receptors in ocular tissues of the anterior segment of the eye, including the iris-ciliary body of rabbit (Chidlow et al., 1998) and human (Martin et al., 1992), suggests that this neurotransmitter may play an important role in the regulation of intraocular pressure (IOP). Serotonin (5-hydroxytryptamine; 5-HT) is also found in the aqueous humor of humans (Veglio et al., 1998) and other mammals (Boerrigter et al., 1992). These observations have generated considerable interest in the role that serotonin might have in aqueous humor dynamics and even whether 5-HT might be involved in the development of ocular hypertension and glaucoma. There have been numerous conflicting reports on the effect of 5-HT and various 5-HT receptor ligands on IOP in the rabbit, dog, and humans. These observed differences in IOP response may be due to species differences, route of administration, or the lack of 5-HT receptor selectivity of the agents evaluated. For example, 5-HT has been shown to lower IOP in rabbits following intravenous injection (Chiang, 1974). However, when injected intracamerally in the rabbit, a rise in IOP was observed (Krootila et al., 1987). Furthermore, topical ocular administration of 5-HT to the rabbit was reported to result in either a decrease (Krootila et al., 1987) or an increase (Meyer-Bothling et al., 1993) in IOP.Article, publication date, and citation information can be found at

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mentioning

confidence: 54%

Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT_1A and 5-HT₂ Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys

May¹,

McLaughlin²,

Sharif³

et al. 2003

J Pharmacol Exp Ther

106

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“…49 Aldous et al 50 also reported a method for resolution of the enantiomers through the recrystallization of N-benzyloxycarbonyl-l-phenalanine-p-nitrophenyl esters. Unfortunately, these developments preceded the modern molecular biology era, and affinity and potency at actual receptors could not be reported at that time.…”

Section: Phenethylamines and Congenersmentioning

confidence: 99%

“…Aldous et al 50 subsequently explored several cyclopropane analogs of substituted amphetamines. Although it was not then possible to measure receptor effects, production of hyperthermia in rabbits as well as producing changes in cat encephaolgram (EEG) were taken as indicators of possible hallucinogenic action, which we now know is correlated with actions at the 5-HT 2A receptor.…”

Section: Effect Of α-Alkylationmentioning

confidence: 99%

Structure–activity relationships of serotonin 5‐HT_2A agonists

Nichols

2012

WIREs Membr Transp Signal

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Of the 14 known types of serotonin receptors one of the most extensively studied is the 5-HT 2A (5-hydroxytryptamine) receptor. In the brain, this receptor plays a key role in regulation of cortical function and cognition, appears to be the principal target for the hallucinogenic/psychedelic drugs such as lysergic acid diethylamide (LSD), and also is a target for the newest atypical antipsychotic agents, which are antagonists or inverse agonists at this site. Among the structure-activity relationships that are known for this receptor type, there are three chemical classes of agonists: tryptamines, ergolines, and phenethylamines. Important structural features are identified for agonist activity and some of these agonists have features in common. In addition to effects at the receptor will be the focus, these drugs are also hallucinogenic (psychedelic) agents, and much of the SAR was developed on the basis of effects in humans, before modern pharmacological techniques were available. A certain amount of our knowledge therefore relies on those human studies.

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“…On the other hand, the more rigid 2-aminoindan and 2-aminotetralin analogs of the Donor-H Donor-Acceptor H-Acceptor DonorH-Acceptor hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM, STP), which also mimic trans conformations, do not elicit hallucinogen-like effects in rat conditioned avoidance studies [33] It seems reasonable to assume that they are unable to interact effectively with the appropriate receptor(s) due, precisely, to their rigidity, perhaps because they cannot mimic the preferred perpendicular orientation of the C8-C9 bond with regard to the benzene ring. However, these rigid molecules fully substitute for MDMA in animal experiments [32], suggesting that MDMA-like activity may be associated with trans conformations of the aminoethyl side chain.…”

Section: Biological Relevancementioning

confidence: 98%

Quantum-chemical, NMR and X-ray diffraction studies on (±)-1-[3,4-(methylenedioxy)phenyl]-2-methylaminopropane

Zapata‐Torres

Cassels

Parra-Mouchet

et al. 2008

Journal of Molecular Graphics and Modelling

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ChemInform Abstract: STRUCTURE‐ACTIVITY RELATIONSHIPS IN PSYCHOTOMIMETIC PHENYLALKYLAMINES

Abstract: Zahlreiche Phenylalkylamine (I) werden in der angedeuteten Weise hergestellt.

Cited by 10 publications

References 1 publication

Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT_1A and 5-HT₂ Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys

Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT_1A and 5-HT₂ Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys

Structure–activity relationships of serotonin 5‐HT_2A agonists

Quantum-chemical, NMR and X-ray diffraction studies on (±)-1-[3,4-(methylenedioxy)phenyl]-2-methylaminopropane

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ChemInform Abstract: STRUCTURE‐ACTIVITY RELATIONSHIPS IN PSYCHOTOMIMETIC PHENYLALKYLAMINES

Abstract: Zahlreiche Phenylalkylamine (I) werden in der angedeuteten Weise hergestellt.

Cited by 10 publications

References 1 publication

Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT1A and 5-HT2 Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys

Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT1A and 5-HT2 Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys

Structure–activity relationships of serotonin 5‐HT2A agonists

Quantum-chemical, NMR and X-ray diffraction studies on (±)-1-[3,4-(methylenedioxy)phenyl]-2-methylaminopropane

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Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT_1A and 5-HT₂ Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys

Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT_1A and 5-HT₂ Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys

Structure–activity relationships of serotonin 5‐HT_2A agonists