Phentermine plus fenfluramine produce cocaine-like discriminative cues
analogs; cocaine; combinations; drug discrimination; fenfluramine; Pharmacology & Pharmacy; phentermine; receptors; Research & Experimental Medicine; serotonin; stimulus properties
Drug discrimination studies were conducted in six male Sprague-Dawley rats trained to discriminate the interoceptive cues produced by 10 mg/kg cocaine in an effort to investigate if there is stimulus generalization to phentermine or phentermine + fenfluramine. Once having reached criterion performance, these rats were tested with lower doses of cocaine and generated a typical dose-response curve allowing for calculation of an ED(50) value: 2.798 mg/kg. Testing of phentermine in doses of 1.25-5.0 mg/kg indicated generalization with the highest dose producing 80% cocaine-appropriate responding and allowing for an ED(50) value of 2.356 mg/kg. When the phentermine doses were tested in combination 2.0 mg/kg fenfluramine, however, there was an increase in the discriminability of the highest phentermine dose and a slight decrease in the ED(50) value of the combination. Thus, administration of phentermine + fenfluramine, having both dopamine-releasing and serotonin-releasing properties, respectively, may mimic the neurochemical activity by which cocaine acts in the central nervous system and may possibly allow for cocaine-like effects as these two drugs see increased use in obesity control.
Schechter M D; McBurney D
Life Sciences
1996
1996-10
Journal Article
<a href="http://doi.org/10.1016/s0024-3205(96)00513-9" target="_blank" rel="noreferrer noopener">10.1016/s0024-3205(96)00513-9</a>
Bis-azaaromatic quaternary ammonium salts as ligands for the blood-brain barrier choline transporter
12-diyl-bis-3-picolinium dibromide; analogs; Bis-quaternary ammonium salts; Blood-brain barrier; Chemistry; Choline transporter; evoked dopamine release; extracellular dopamine; hyperactivity; mediated transport; n; n'-dodecane-1; nicotinic-receptor antagonist; nucleus-accumbens; Pharmacology & Pharmacy; rat; tobacco dependence; vector
A series of bis-azaaromatic quaternary ammonium compounds containing flexible polymethylenic linkers as well as conformationally restricted linkers were evaluated for their affinity for the blood-brain barrier choline transporter (BBB-ChT). The preliminary structure-activity relationships obtained from this study suggest that incorporating a linear, conformationally restricted linker into the molecule improves affinity for the BBB-ChT. (C) 2010 Elsevier Ltd. All rights reserved.
Zheng G R; Zhang Z F; Lockman P R; Geldenhuys W J; Allen D D; Dwoskin L P; Crooks P A
Bioorganic & Medicinal Chemistry Letters
2010
2010-06
Journal Article
<a href="http://doi.org/10.1016/j.bmcl.2010.04.098" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2010.04.098</a>
Presence and characteristics of receptors for D-Trp(6) luteinizing hormone releasing hormone and epidermal growth factor in human ovarian cancer
analogs; antagonists; binding-sites; chemotherapy; EGF receptors; estrogen; expression; gnrh; human endometrial carcinoma; LH-RH analogs; LH-RH receptors; Oncology; ovarian-cancer; rat; somatostatin
This study was undertaken to establish the presence and characteristics of receptors for [D-Trp(6)]LH-RH on the membranes of human ovarian cancer. Specific binding of [I-125, D-Trp(6)]LH-RH was found in 29 of 37 (78.4%) ovarian cancers and in 6 of 11 (54.5%) non-malignant human ovaries. Ligand binding was dependent on time and plasma membrane concentration in a fashion expected of a peptide hormone. Saturation, kinetic and displacement data were consistent with the presence of a highly specific, single class of non-cooperative binding site. On the basis of receptors affinity, LH-RH-receptor-positive ovarian cancers could be divided into two groups: high affinity group (K-d=2.7+/-0.60 nM; B-max=0.46+/-0.07 pmol/mg membrane protein) comprising 55% of tumors, and low affinity group (K-d=78.0+/-19.6 nM; B-max=9.44+/-2.68 pmol/mg membrane protein) which included 45% of tumors. LH-RH antagonist Cetrorelix showed an affinity to LH-RH receptors on ovarian cancers 14 times higher than the agonist [D-Trp(6)]LH-RH. Using I-125-epidermal growth factor, specific high affinity receptors were also detected in membranes from 13 of 24 (54%) ovarian cancers and 5 of 11 (45%) non-malignant ovaries. The demonstration of LH-RH receptors in human ovarian cancers provides a rationale for the use of therapeutic approaches based on LH-RH analogues in this malignancy. The probable involvement of growth factors in the development of ovarian cancers suggests the merit of trying a combined therapy based on analogs of LH-RH and somatostatin for this carcinoma.
Srkalovic G; Schally A V; Wittliff J L; Day T G; Jenison E L
International Journal of Oncology
1998
1998-03
Journal Article
n/a
Synthesis of 3 beta-(4- I-125 Iodophenyl)tropane-2 beta-pyrrolidine carboxamide ( I-125 RTI-229)
acid isopropyl ester; analogs; Biochemistry & Molecular Biology; brain; Chemistry; chloramine-T; cocaine; dopamine transporter; high-affinity; iodine-125 labelling; iododestannylation; ligand; nonhuman primates; Pharmacology & Pharmacy; radioiodination; RTI-229
A WIN 35,055-2 analog, 3 beta-(4-iodophenyl)tropane-2 beta-pyrrolidine carboxamide (RTI-229), has been radiolabelled with iodine-125 by radioiododestannylation of the corresponding trimethyltin derivative using carrier-free sodium iodide-125 as the isotope source. Purification by reversed-phase HPLC gives [I-125]RTI-229 in good yield (89.4%) with high radiochemical purity (>99%) and high specific activity (2125 mCi/mu mol, 78.6 GBq/mu mol, based on the specific activity of the (NaI)-I-125 used).
Zhong D S; Kotian P; Wyrick C D; Seltzman H H; Kepler J A; Boja J W; Kuhar M J; Carroll F I
Journal of Labelled Compounds & Radiopharmaceuticals
1999
1999-03
Journal Article
n/a
Identification Of Multifunctional Small Molecule-based Reversible Monoamine Oxidase Inhibitors
analogs; Biochemistry & Molecular Biology; crystal-structures; drugs; mechanism; neuroprotection; parkinsons-disease; Pharmacology & Pharmacy; rasagiline; targets
Geldenhuys W J; Ko K S; Stinnett H; Van der Schyf C J; Lim M H
Medchemcomm
2011
2011-11
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1039/c1md00176k" target="_blank" rel="noreferrer noopener">10.1039/c1md00176k</a>
Predictive Screening Model For Potential Vector-mediated Transport Of Cationic Substrates At The Blood-brain Barrier Choline Transporter
12-diyl-bis-3-picolinium dibromide; analogs; Carrier-mediated transport; central-nervous-system; Chemistry; Drug bioavailability; Drug screening; evoked dopamine; extracellular dopamine; high-affinity choline; molecular-field analysis; n; n'-dodecane-1; Nicotinic receptor antagonists; Nicotinic receptor antagonists; perfusion technique; Pharmacology & Pharmacy; Quaternary ammonium; quaternary ammonium analogs; rat; release; Smoking cessation; striatal synaptosomes
Geldenhuys W J; Manda V K; Mittapalli R K; Van der Schyf C J; Crooks P A; Dwoskin L P; Allen D D; Lockman P R
Bioorganic & Medicinal Chemistry Letters
2010
2010-02
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.bmcl.2009.12.079" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2009.12.079</a>