Human serotonin transporter (hSERT), a membrane protein from the neurotransmitter sodium symporter family, is implicated in depression disorder and has been the primary target of antidepressant discovery research for several decades. Since the currently available antidepressants may cause adverse effects and have several limitations, novel drugs are highly desired. However, the efforts to develop better therapeutics are hampered by the lack of a crystal structure of hSERT. Knowledge of the binding site of the drug and its orientation in the protein is crucial in structure-based drug discovery. We employed a novel computational protocol comprised of active site detection, docking, scoring, molecular dynamics simulations, and absolute binding free energy (ABFE) calculations to elucidate the binding site and the binding mode of a dual hSERT/5HT-1A blocker SSA-426 and our in-house hSERT inhibitor DJLDU-3-79 in hSERT. Through this approach, we propose that both of these inhibitors bind in the S1 pocket of hSERT and in a similar orientation. This disproves the earlier hypothesis that both these inhibitors bind in the S2 site; however, we are in agreement with the earlier hypothesis that both of the ligands orient similarly. Further, we resolved the ambiguity in binding energies and binding trends of the tricyclic antidepressant drugs clomipramine, imipramine, and desipramine with leucine transporter (LeuT) (a bacterial homologue of hSERT) through relative binding free energy (RBFE) calculations. Based on our RBFE results, we proposed that clomipramine should have the highest affinity for LeuT, followed by imipramine and desipramine. Finally, to achieve accuracy in binding energy estimations and to perform all CHARMM simulations, we developed CHARMM general force field parameters (CGenFF) for fifteen monoamine transporter ligands. / Bayer School of Natural and Environmental Sciences; / Chemistry and Biochemistry / PhD; / Dissertation;

No description available.

Thesis (M.Sc.) -- University of Adelaide, Dept.of Human Physiology and Pharmacology, 1971.

Thesis (M.S.)--Youngstown State University, 1998. / Includes bibliographical references (leaves 43-52).

Stuttgart, Univ., Diss., 2000.

Thesis--University of Wisconsin--Madison. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 142-162).

No description available.

Note:

Thesis (Ph. D.)--University of Wisconsin--Madison, 1975. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 114-133).

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.