Central serotonin (5-hydroxytryptamine, 5-HT) receptors are classified into 5-HT₁ (defined by [³H]5-HT binding) and 5-HT₂ (defined by [³H]ketanserin binding). Antagonists selective for 5-HT₁ receptors or 5-HT₁(A) and 5-HT₁(B) subtypes are currently unavailable. To develop such antagonists, a study of derivatives of tryptamine (TRYP) (which are generally selective for 5-HT₁ sites) was undertaken. For amino-N-substituted TRYPs at 5-HT₁ sites, although overall potency decreases with increased N-alkyl substituent size (up to N,N-di-iPr), discrimination between subtypes of 5-HT₁ sites increases. Compounds such as N,N-di-iPr-TRYP (DIPT) and 3-(2-morpholinoethyl)indole (MEI) recognize 30% of [³H] 5-HT binding sites with high affinity (Ki<50 nM) , the rest with low affinity (Ki >4000 nM). For both the DIPT (agonist) and MEI (antagonist) series, incorporating 5-oxy substituents resulted in rank order to overall 5-HT₁ potency of 5 - OH>MeO=5H>BzO; however, the 5-oxy compounds lost the high-affinity recognition component shown by DIPT and MEI. Incorporation of an additional hetero-aromatic moiety gave amino-N-aryl substituted TRYPs (prototype AHR 1709). These were (1) highly selective for 5-HT₁(A) sites (Ki = 10 - 200 nM) over 5-HT₁(B) sites (Ki > 3000 nM), (2) potent at the 5-HT site & (3) vascular antagonists of 5-HT. Pharmacophoric differences between 5-HT₁, 5-HT₁(A) and 5-HT₂ sites were studied with rigid analogs. Racemic partial ergolines RU 27849 and RU 28306 showed diminished potency compared to TRYPs at 5-HT₁ sites, but were equipotent to homologous TRYPs at the 5-HT₂ site. At all three sites, 3-(tetrahydropyridyl)indoles (THPIs) were the most potent rigid analogs studied. A non-ergoline-like constrained analog of TRYP was synthesized and was even less potent than RU 27849 at 5-HT₁ sites, but was 4-5 times as potent as TRYP & RU 27849 at the 5-HT₂ site. While enhancing affinity for 5-HT₁ sites, the 5-MeO group can give reduced affinity for 5-HT₂ sites, thus enhancing 5-HT₁ selectivity. 5-Unsubstituted compounds may be best for 5-HT₂ selectivity. A study of 5-HT agonists in the canine basilar artery (CBA) suggests the contraction in vitro is mediated by a receptor similar to the 5-HT₁(A) binding site; 5-HT₂ receptors may also be present. Theoretical models for the production of apparent noncompetitive antagonism to 5-HT in the CBA are also examined. Syntheses of tryptamine derivatives and a conformationally constrained analog of TRYP are described.

No description available.

A dissertation submitted to the Faculty of Medicine, University of the Witwatersrand, Johannesburg, in fulfilment of requirements for the degree of Medicine in Psychiatry. Johannesburg, March 1991. / In the first part of the dissertation a literature survey is done, looking at 1. An overview of dysthymic disorder. 2. An overview of serotonin and its involvement in psychiatric disorder [Abbreviated Abstract. Open document to view full version]

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 4 uppsatser.

Bibliography: leaves 118-161 / 161 [46] leaves : ill ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 1984

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

The naturally occuring ergot alkaloids of the fungus, Claviceps purpurea, and their many derivatives have been of neuropharmacological interest for many years because of their ability to affect peripheral and central adrenergic and serotonergic systems. More recently, selected compounds such as lergotile (2-chloro-6-methyl ergoline-8-beta acetonitrile) and and bromocriptine (2-bromo-alpha-ergocryptine), have been given additional attention due to their possible therapeutic potential in the treatment of parkinson’s disease, acromegaly and other disorders. There have been considerable data published attempting to establish the mechanism(s) whereby the ergot compounds exert their effects. A large portion of these experiments involves the interaction of ergot compounds with dopaminergic systems. This is a logical course of study, since many of the actions of the ergot compounds mimic the actions of compounds known to affect dopaminergic neurons, e.g. antagonists such as the phenothiazines and butyrophenones and agonists such as levodopa and apomorphine. In the last decade, much attention also has been focused on the role of serotonin (5-hydroxytryptamine) in the mediation of dopaminergic systems. There have been many conflicting reports published as to the role of serotonin but it is still uncertain whether or not serotonin does indeed play a role. The present study investigates two dopaminergic effects of the standard dopamine agonist apomorphine and the ergoline lergotrile and the similarities or differences that exist when serotonergic function is altered.

This thesis explored the mechanism of action of MPTP and its toxic metabolite, MPP⁺, and compared it to the mechanism of action of haloperidol metabolites, some of which are found in schizophrenic patients. Experiments assessed the effects of these compounds on several aspects of amine uptake in mouse brain synaptosomes. Both MPTP and MPP⁺ were inhibitors of labeled neurotransmitter (serotonin and dopamine) uptake consistent with previous studies. MPP⁺ had a higher inhibitory potency in the dopaminergic system, while MPTP had a higher inhibitory potency in the serotonergic system. Haloperidol metabolites (HPP⁺, R-HPP⁺, and HPTP) also inhibited both amine transport systems with a greater affinity for the serotonergic system. Additional studies demonstrated that all of the above compounds showed reversible inhibition of serotonin uptake following drug removal by centrifugation and resuspension. In the dopaminergic system, both MPTP and MPP⁺ were reversible; however, HPP⁺ was not. This finding suggests that HPP⁺ treatment may result in irreversible poisoning of the nerve terminal or it may demonstrate a slow off-rate for its interaction with the dopamine transporter. Furthermore, HPP+ showed non-competitive inhibition of both serotonin and dopamine uptake. Amine uptake in the presence and absence of HPP* had a decreased maximal inhibitory effect and no potency change. The reversible inhibition of serotonin uptake by HPP⁺ might suggest competitive inhibition, but apparently, the comparative rates of binding and unbinding of HPP⁺ and serotonin resulted in a non-competitive interaction. These experiments support the use of MPTP as a model system for analyzing the neurotoxic potential of toxins, drug metabolites, and pesticides. The similar in vitro potencies suggest that the haloperidol derivatives could have effects similar to those of MPP⁺ in vivo. / Master of Science

D. Tech. Chemistry. / Aims to isolate and characterise mesembrine-type alkaloids from S. tortuosum for use as reference standards ; develop and validate analytical methods for the accurate determination of mesembrine-type alkaloids in S. tortuosum samples and commercial products for quality control purposes ; investigate inter-species variation of alkaloids in endemic Sceletium species ; establish the variation of mesembrine-type alkaloids within and between different populations of S. tortuosum specimens and hence identify various chemotypes ; determine the variations of the target alkaloids in S. tortuosum commercial products purchased from various suppliers ; determine the mesembrine-type alkaloid content of the combustion products from S. tortuosum; and to evaluate the in vitro permeation of the alkaloids across oral and intestinal mucosa.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 5 uppsatser.