ABSTRACT
A series of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5-(6H)ones and 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines was shown to exhibit 5-HT2C agonist binding and functional activity. Compound 21R inhibited food intake over 2 h in fasted, male Sprague Dawley rats with ED50 values of 2 mg/kg (i.p.) and 10 mg/kg (p.o.).
Subject(s)
Appetite Depressants/chemical synthesis , Pyrazines/chemical synthesis , Quinoxalines/chemical synthesis , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/chemical synthesis , Animals , Appetite Depressants/pharmacology , Eating/drug effects , Male , Pyrazines/pharmacology , Quinoxalines/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2C , Serotonin Receptor Agonists/pharmacology , Structure-Activity RelationshipABSTRACT
Synthesis and SAR of N-[4-[(4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-y l)carbonyl]phenyl]benzamides as arginine vasopressin (AVP) receptor antagonists are discussed. Potent orally active AVP receptor antagonists are produced when the benzamide moiety contains a phenyl group at the 2-position. Similar analogues of 4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepine and VPA-985 are reported.
Subject(s)
Arginine Vasopressin/antagonists & inhibitors , Azepines/chemical synthesis , Azepines/pharmacology , Animals , Arginine Vasopressin/metabolism , Azepines/chemistry , Azepines/metabolism , Rats , Receptors, Vasopressin/metabolism , Structure-Activity RelationshipABSTRACT
The synthesis of several bioisosteric analogs based on the 3-OH-phenoxyethylamine dopamine D2 agonist template (i.e., 3) is described. The benzimidazol-2-ones and benzthioimidazol-2-ones (7-10) and 2-trifluoromethyl-benzimidazole (13) were observed to have excellent affinity for the D2 receptor.
Subject(s)
Benzimidazoles/chemical synthesis , Dopamine Agents/chemical synthesis , Receptors, Dopamine D2/drug effects , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Dopamine Agents/chemistry , Dopamine Agents/pharmacology , Mice , Motor Activity/drug effectsABSTRACT
Synthesis and structure-activity relationships (SAR) of arginine vasopressin receptor (AVP) antagonists are described. Potent and orally active compounds are prepared when tricyclic 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine moiety in VPA-985 1 is replaced with a compound 7 or 12.
Subject(s)
Antidiuretic Hormone Receptor Antagonists , Azepines/chemical synthesis , Azepines/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Benzazepines/chemical synthesis , Thiophenes/chemical synthesis , Administration, Oral , Animals , Benzazepines/pharmacology , Fibroblasts , Inhibitory Concentration 50 , Mice , Pyrroles , Structure-Activity Relationship , Thiophenes/pharmacologyABSTRACT
Synthesis and structure-activity relationships (SAR) of orally active arginine vasopressin (AVP) receptor antagonists are discussed. Potent and orally active AVP receptor antagonists are produced when ring A of VPA-985 (1) is replaced with a 3-pyridinyl unit (2b).
Subject(s)
Aminopyridines/chemical synthesis , Aminopyridines/pharmacology , Antidiuretic Hormone Receptor Antagonists , Azepines/chemical synthesis , Benzamides/chemical synthesis , Benzodiazepines/chemical synthesis , Benzodiazepines/pharmacology , Aminopyridines/urine , Animals , Azepines/pharmacology , Benzamides/pharmacology , Benzodiazepines/urine , Inhibitory Concentration 50 , Kidney/drug effects , Liver/drug effects , Pyrroles , RatsSubject(s)
Arginine Vasopressin/antagonists & inhibitors , Receptors, Vasopressin/metabolism , Administration, Oral , Animals , Arginine Vasopressin/deficiency , Azepines/administration & dosage , Azepines/chemical synthesis , Azepines/metabolism , Azepines/pharmacology , Benzamides/administration & dosage , Benzamides/chemical synthesis , Benzamides/metabolism , Benzamides/pharmacology , Blood Platelets/metabolism , Body Water/metabolism , Cell Line , Cell Membrane/metabolism , Dogs , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Kidney/metabolism , Liver/metabolism , Osmolar Concentration , Pyrroles , Rats , Sodium/blood , Structure-Activity Relationship , Urine/chemistryABSTRACT
Described in this report is a systematic study which led to the identification of two new dopamine D2 partial agonists (5 and 17). Phenols 5 and 17 represent prototypes of two new classes of D2 partial agonists as well as templates for the future design of novel dopaminergic agents.
Subject(s)
Dopamine Agonists/chemistry , Phenols/chemistry , Piperazines/chemistry , Dopamine Agonists/pharmacology , Phenols/chemical synthesis , Phenols/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Receptors, Dopamine D2/agonists , Structure-Activity RelationshipABSTRACT
The synthesis of several bioisosteric analogs based on the 3-OH-N1-phenylpiperazine dopamine D2 agonist template (i.e., 4) is described. The indolone (5) and 2-CF3-benzimidazole (13) were observed to have excellent affinity for the D2 receptor. Several D4 selective compounds were also identified. Molecular modeling studies and a putative bioactive conformation are discussed.
Subject(s)
Dopamine Agents/chemical synthesis , Dopamine Agents/pharmacology , Piperazines/chemistry , Piperazines/pharmacology , Psychotropic Drugs/chemical synthesis , Psychotropic Drugs/pharmacology , Animals , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Corpus Striatum/ultrastructure , Dopamine Agonists/chemical synthesis , Dopamine Agonists/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Kinetics , Rats , Receptors, Dopamine D2/agonists , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3 , Structure-Activity Relationship , Templates, GeneticSubject(s)
Arginine Vasopressin/antagonists & inhibitors , Azepines/pharmacology , Benzamides/pharmacology , Receptors, Vasopressin/metabolism , Animals , Antidiuretic Hormone Receptor Antagonists , Blood Pressure/drug effects , Cyclic AMP/metabolism , Dogs , Heart Failure/physiopathology , Humans , Hyponatremia/etiology , Hyponatremia/physiopathology , Inappropriate ADH Syndrome/physiopathology , Kidney/drug effects , Kidney/physiology , Kidney/physiopathology , PyrrolesABSTRACT
A series of 2-(aminomethyl)chromans (2-AMCs) was synthesized and evaluated for their affinity and selectivity for both the high- and low-affinity agonist states (D2High and D2Low, respectively) of the dopamine (DA) D2 receptor. The 7-hydroxy-2-(aminomethyl)chroman moiety was observed to be the primary D2 agonist pharmacophore. The 2-methylchroman moiety was discovered to be an entirely novel scaffold which could be used to access the D2 agonist pharmacophore. Attaching various simple alkyl and arylalkyl side chains to the 7-hydroxy 2-AMC nucleus had significant effects on selectivity for the D2High receptor vs the 5HT1A and alpha 1 receptors. A novel DA partial agonist, (R)-(-)-2-(benzylamino)methyl)chroman-7-ol [R-(-)-35c], was identified as having the highest affinity and best selectivity for the D2High receptor vs the alpha 1 and 5HT1A receptors. Several regions of the 2-AMC nucleus were modified and recognized as potential sites to modulate the level of intrinsic activity. The global minimum conformer of the 7-hydroxy-2-AMC moiety was identified as fulfilling the McDermed model D2 agonist pharmacophoric criteria and was proposed as the D2 receptor-bound conformation. Structure-activity relationships gained from these studies have aided in the synthesis of D2 partial agonists of varying intrinsic activity levels. These agents should be of therapeutic value in treating disorders resulting from hypo- and hyperdopaminergic activity, without the side effects associated with complete D2 agonism or antagonism.
Subject(s)
Chromans/chemical synthesis , Dopamine Agents/chemical synthesis , Receptors, Dopamine D2/agonists , Animals , CHO Cells , Chromans/chemistry , Chromans/pharmacology , Cricetinae , Dopamine Agents/chemistry , Dopamine Agents/metabolism , Dopamine Agents/pharmacology , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Mice, Inbred Strains , Models, Molecular , Molecular Structure , Motor Activity/drug effects , Protein Binding , Rats , Rats, Sprague-Dawley , Receptors, Serotonin/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
In the present study, the effects of chronic lithium pre-treatment (30 days) on penile erection (PE) induced by bromocriptine were investigated in rats. Intraperitoneal administration of the dopamine receptor agonist, bromocriptine (4-32 mg/kg) induced PE in a biphasic manner. The maximum response was obtained with 8 mg/kg of bromocriptine and the effect was decreased with increasing doses of the drug from 8 to 32 mg/kg. When animals were pre-treated with different doses of the D-1 dopamine receptor antagonist, SCH 23390, or the D-2 dopamine receptor antagonist, sulpiride, the PE response was decreased. The response induced by bromocriptine (4-32mg/kg) was reduced in animals pre-treated with chronic lithium. SCH 23390 did not produce a larger inhibitory effect on the bromocriptine response in animals pre-treated with chronic lithium, but the inhibitory effect of sulpiride was increased in this condition. It is concluded that chronic lithium treatment may alter the D-1/D-2 receptor activity and inhibit bromocriptine-induced PE.
ABSTRACT
1. The effects of chronic lithium pretreatment (600 mg/l in drinking rats, 30 days) on penile erection (PE) induced by apomorphine were investigated in rats. This treatment resulted in a serum Li concentration after 30 days of 0.31 +/- 0.01 mmol/l. 2. Subcutaneous (s.c.) administration of mixed D1/D2 dopamine receptor agonist apomorphine (0.05-0.5 mg/kg) induced PE in a biphasic manner. The maximum effect was obtained with 0.1 mg/kg of the drug while the response decreased with increasing doses of apomorphine from 0.1 to 0.5 mg/kg. 3. Pretreatment of animals with 0.0125-0.1 mg/kg of D1 dopamine receptor antagonist SCH 23390 or D2 dopamine receptor antagonist sulpiride (12.5-100 mg/kg) decreased apomorphine-induced PE. Combination of SCH 23390 (0.025 mg/ kg) with sulpiride (12.5 mg/kg) caused a stronger inhibitory effect on apomorphine response. This indicates that both D1 and D2 dopamine receptors may be involved in PE induced by apomorphine. 4. The response induced by apomorphine (0.05-0.05 mg/kg) was decreased in animals pretreated with chronic lithium. The inhibitory effect of sulpiride on apomorphine response, increased in animals pretreated with lithium, in contrast the inhibitory effect of SCH 23390 did not change in this condition. However, a combination of SCH 23390 with sulpiride increased inhibitory effect on apomorphine response in lithium pretreated rats. 5. It is concluded that chronic lithium inhibits PE induced by dopaminergic mechanism(s).