Subject(s)
Estradiol Congeners/chemical synthesis , Indoles/chemical synthesis , Animals , Bone Density/drug effects , Cell Line , Estradiol Congeners/chemistry , Estradiol Congeners/metabolism , Estradiol Congeners/pharmacology , Female , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Models, Molecular , Organ Size , Ovariectomy , Radioligand Assay , Rats , Structure-Activity Relationship , Transfection , Uterus/drug effectsABSTRACT
A series of 2-amino-(phosphonoalkyl)-1H-benzimidazole-2-alkanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H]CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Several compounds of the AP-6 type demonstrated potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular, [R(-)]-2-amino-3-(5-chloro-1-phosphonomethyl-1H-benzoimidazol-2-yl)-propionic acid (1) displayed an IC(50) value of 7.1 nM in the [3H]CPP binding assay and an ED(50) value of 0.13 mg/kg (ip) in the NMDA lethality model. Compound 1, when administered intravenously as a single bolus dose of 3 mg/kg following permanent occlusion of the middle cerebral artery in the rat, reduced the volume of infarcted brain tissue by 45%. These results support a promising therapeutic potential for compound 1 as a neuroprotective agent.
Subject(s)
Benzimidazoles/chemical synthesis , Excitatory Amino Acid Antagonists/chemical synthesis , Neuroprotective Agents/chemical synthesis , Propionates/chemical synthesis , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Arterial Occlusive Diseases/complications , Benzimidazoles/chemistry , Benzimidazoles/metabolism , Benzimidazoles/pharmacology , Binding, Competitive , Brain/metabolism , Brain/pathology , Carotid Artery Diseases/complications , Drug Evaluation, Preclinical , Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/metabolism , Excitatory Amino Acid Antagonists/pharmacology , In Vitro Techniques , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/etiology , Infarction, Middle Cerebral Artery/pathology , Male , Mice , Models, Molecular , Neuroprotective Agents/chemistry , Neuroprotective Agents/metabolism , Neuroprotective Agents/pharmacology , Organophosphonates , Propionates/chemistry , Propionates/metabolism , Propionates/pharmacology , Radioligand Assay , Rats , Rats, Inbred F344 , Receptors, N-Methyl-D-Aspartate/metabolism , StereoisomerismABSTRACT
A series of 2-phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives was examined for the ability to inhibit both rat brain imipramine receptor binding and the synaptosomal uptake of norepinephrine (NE) and serotonin (5-HT). Neurotransmitter uptake inhibition was highest for a subset of 2-phenyl-2-(1-hydroxycyclohexyl)dimethylethylamines in which the aryl ring has a halogen or methoxy substituent at the 3- and/or 4-positions. Potential antidepressant activity in this subset was assayed in three rodent models--the antagonism of reserpine-induced hypothermia, the antagonism of histamine-induced ACTH release, and the ability to reduce noradrenergic responsiveness in the rat pineal gland. An acute effect seen in the rat pineal gland with several analogues, including 1-[1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol (23) and 1-[2-(dimethylamino)-1)-(4-methoxyphenyl)ethyl]cyclohexanol (4), was taken as a possible correlate of a rapid onset of antidepressant activity. Compound 4 (venlafaxine) is presently undergoing clinical evaluation.
Subject(s)
Antidepressive Agents/chemical synthesis , Phenethylamines/chemical synthesis , Adrenocorticotropic Hormone/metabolism , Animals , Antidepressive Agents/metabolism , Binding, Competitive , Biological Assay , Biological Transport , Brain/metabolism , Chemical Phenomena , Chemistry, Physical , Crystallography , Hypothermia/chemically induced , Imipramine/metabolism , In Vitro Techniques , Models, Molecular , Neurotransmitter Agents/metabolism , Norepinephrine/metabolism , Phenethylamines/metabolism , Rats , Receptors, Adrenergic, beta/metabolism , Receptors, Serotonin/metabolism , Reserpine/antagonists & inhibitors , Serotonin/metabolism , Structure-Activity Relationship , X-Ray DiffractionABSTRACT
The synthesis and structure-activity relationships of a number of 1,3-bis(aryloxy)propanes, which are in vivo antagonists of LTD4 in the guinea pig, are described. One of these compounds, 4 (Wy-44,329), was not only approximately equipotent with the standard 1 (FPL 55712) in the LTC4 (ID50 = 0.17 and 0.23 mg/kg iv, respectively) and LTD4 (ID50 = 0.11 and 0.15 mg/kg iv, respectively) challenge models but also possessed greater potency in the ovalbumin challenge model (ID50 = 0.47 mg/kg and 4.1 mg/kg iv, respectively) and a longer duration of action. This compound was a competitive LTD4 antagonist on guinea pig ileum (pA2 = 9.4) and possessed mediator release (rat PCA, ID50 = 0.26 mg/kg iv) and 5-lipoxygenase (IC50 = 32 microM vs. 5-HETE) inhibitory activities.
Subject(s)
Phenyl Ethers/chemical synthesis , SRS-A/antagonists & inhibitors , Animals , Guinea Pigs , Indicators and Reagents , Magnetic Resonance Spectroscopy , Muscle Contraction/drug effects , Muscle, Smooth/physiology , Phenyl Ethers/pharmacology , SRS-A/chemical synthesis , Spectrophotometry, Infrared , Structure-Activity RelationshipABSTRACT
Seven derivatives of LH-RH, representing the [D-Ala6] or [D-Trp6] series, with or without a Fujino modification, were evaluated for ovulation-inducing (agonist and post-coital contraceptive activity in rats. Six of these analogues had a high degree of agonist and pregnancy-terminating potency. In general, several modifications can result in a particular series of composite molecules that possess a biologic potency greater than each of its predecessors; this correlation of structure with activity was more consistent in the [D-Ala6]-series than in the [D-Trp6]-series. The relationship between structural modifications, resistance to enzyme degradation (based on literature reports) and increased biologic potency is discussed.
Subject(s)
Contraceptives, Postcoital, Hormonal/pharmacology , Contraceptives, Postcoital/pharmacology , Gonadotropin-Releasing Hormone/analogs & derivatives , Ovulation Induction , Animals , Female , Gonadotropin-Releasing Hormone/pharmacology , Male , Pregnancy , Rats , Structure-Activity RelationshipSubject(s)
Pancreas/metabolism , Pituitary Gland/metabolism , Somatostatin/analogs & derivatives , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/metabolism , Dogs , Glucagon/blood , Growth Hormone/metabolism , Pancreas/drug effects , Pituitary Gland/drug effects , Rats , Time FactorsABSTRACT
Two varients of LH-RH, less than Glu-D-Phe-Trp-D-Ala-Leu-Arg-Pro-Gly-NH2 (I) and less than Glu-D-Phe-Trp-Ser-Tyr-D-Ala-Leu-Arg-Pro-NHCH2CH3 (II), have been synthesized by solid-phase methods. Both peptides strongly inhibit the LH-RH induced secretion of LH in an in vitro assay; however, only I proved effective in preventing ovulation in the 4-day cycling rat.
Subject(s)
Gonadotropin-Releasing Hormone/analogs & derivatives , Luteinizing Hormone/antagonists & inhibitors , Ovulation/drug effects , Animals , Cells, Cultured , Depression, Chemical , Female , Gonadotropin-Releasing Hormone/chemical synthesis , Gonadotropin-Releasing Hormone/pharmacology , In Vitro Techniques , Luteinizing Hormone/blood , Pituitary Gland/drug effects , RatsABSTRACT
Ten analogs of luteinizing hormone-releasing hormone (LH-RH) substituted in position 2 with D-amino acids and at 6 with either a D-amino acid or a nonasymmetric amino acid were synthesized by solid-phase methodology and assayed for antiovulatory activity. [D-Phe2]-LH-RH substituted in the 6 position with D-Ala, D-Leu, D-Arg, D-(Ph)Gly, D-Phe, or 2-Me-Ala possessed varying degrees of antiovulatory activity. [D-p-F-Phe2-D-Ala6]-LH-RH was one of the most active antiovulatory compounds, while the [D-p-Cl-Phe2-D-Ala6]-LH-RH analog was devoid of activity at a comparable dose.
