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J W Kebabian

Publications and source records attributed to J W Kebabian.

At least 19 recordsLinked to original sources
PubMed1992

A-77636: a potent and selective dopamine D1 receptor agonist with antiparkinsonian activity in marmosets.

A-77636, ((1R,3S) 3-(1'-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benz opyran hydrochloride), is a selective dopamine D1 receptor agonist. In a battery of receptor binding assays, A-77636 shows the highest affinity (pKi = 7.40 +/- 0.09; Ki = 39.8 nM) for the dopamine D1 receptor. A-77636 is an agonist at the dopamine D1 receptors in the fish retina (pEC50 = 8.13; EC50 = 1.1 nM; intrinsic activity = 102% of dopamine) and the rat caudate-putamen (pEC50 = 8.97; intrinsic activity = 134% of dopamine). The compound is functionally inactive at dopamine D2 receptors (EC50 > 10 microM). In rats with unilateral 6-OHDA (6-hydroxydopamine) lesions of the nigro-striatal dopaminergic pathway, A-77636 elicits prolonged (> 20 h) contralateral turning that is blocked by SCH 23390, a D1 receptor antagonist, but not by haloperidol at doses selective for the dopamine D2 receptor. Higher doses of A-77636 produce forelimb clonus in rats and mice. When tested in marmosets treated with MPTP to induce a parkinsonian-like state, A-77636 increases locomotor activity and decreases the severity of the parkinsonian-like symptoms: the compound is active after either subcutaneous or oral administration. A-77641, the optical antipode of A-77636, has a lower affinity towards the dopamine D1 receptor (pKi = 5.14, Ki = 7200 nM), is less potent as a dopamine D1 receptor agonist (pEC50 = 5.65; EC50 = 2200 nM), fails to elicit turning in the 6-OHDA-lesioned rat, and lacks antiparkinsonian efficacy in the MPTP-treated marmoset.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

A68930: a potent agonist specific for the dopamine D1 receptor.

A68930, [1R, 3S] 1-aminomethyl-5,6-dihydroxy-3-phenylisochroman HCl, is a potent, partial agonist in the dopamine-sensitive adenylate cyclase model of the D1 dopamine receptor in fish retina. In the rat caudate-putamen model of the D1 dopamine receptor, A68930 is a potent (EC50 2.1 nM) full agonist. In contrast, A68930 is a much weaker (EC50 = 3,920 nM) full agonist in a biochemical model of the D2 dopamine receptor. A68930 also displays weak 2 agonist activity but the molecule is virtually inactive at the 1 and beta-adrenoceptors. When tested in rats bearing a unilateral 6-OHDA lesion of the nigro-neostriatal neurons, A68930 elicits prolonged (> 20 hr) contralateral turning.

Adenylyl Cyclases↗
PubMed1992

Multiple dopamine receptors and their implications in medicine.

Two categories of dopamine receptor were identified with classical pharmacological and biochemical techniques. Five different molecular species of dopamine receptor have been identified with molecular biological techniques. Each of the these five receptors can be assigned to one of the two classically identified dopamine receptor categories. The biology of the dopamine receptors can be investigated with molecular biological techniques. Recent pharmacological investigations show that the D1 dopamine receptor may be an important site of action for antiparkinsonian drugs.

Alcoholism↗
PubMed1992

Phosphorylation of DARPP-32 and protein phosphatase inhibitor-1 in rat choroid plexus: regulation by factors other than dopamine.

The molecular mechanisms underlying regulation of fluid production by secretory epithelia such as the choroid plexus are poorly understood. Two cAMP-regulated inhibitors of protein phosphatase-1, inhibitor-1 (I1) and a dopamine- and cAMP-regulated phosphoprotein, M(r) = 32,000 (DARPP-32), are enriched in the choroid plexus. We show here that these two phosphoproteins are colocalized in choroid plexus epithelial cells. We have developed a novel method for studying the phosphorylation state of DARPP-32 and I1 in intact cells, using a phosphorylation state-specific monoclonal antibody. Several drugs and hormones that are known to alter fluid secretion and that increase cAMP levels (forskolin, isoproterenol, vasoactive intestinal peptide) or cGMP levels (atrial natriuretic peptide) or that may use additional second messenger pathways (5-HT), increase the phosphorylation of I1 and DARPP-32 in rat choroid plexus. In contrast, dopamine does not alter cAMP and cGMP levels, or I1 and DARPP-32 phosphorylation. Our results indicate that DARPP-32, known to be regulated by dopamine in a number of tissues, can be phosphorylated in response to non-dopaminergic factors, including hormones acting through non-cAMP-dependent pathways. Our results also raise the possibility that inhibition of phosphatase-1, as a result of I1 and DARPP-32 phosphorylation, might be part of a final common pathway in the action of several factors that are known or thought to alter cerebrospinal fluid production.

Amino Acid Sequence↗
PubMed1991

Rapid reversal of denervation supersensitivity of dopamine D1 receptors by l-dopa or a novel dopamine D1 receptor agonist, A68930.

The present report describes the effects of sub-chronic treatment with l-dopa or with a recently characterized, selective dopamine D1 receptor agonist (A68930) on the denervation-induced behavioral supersensitivity of the dopamine D1 receptor. Rats with unilateral 6-OHDA lesions of the nigrostriatal pathway, when treated for four successive days with l-dopa + carbidopa show robust contralateral rotation on each day. However, after three days of l-dopa + carbidopa treatment lesioned animals show a significant loss of behavioral supersensitivity to the dopamine D1-selective agonists, A68930 and SKF38393. When lesioned animals were treated daily with A68930, by the second day they showed a virtually complete loss of responsiveness to a dose of the dopamine D1 agonist which previously produced near maximal rotation. In contrast, locomotor hyperactivity to A68930 by intact rats was undiminished over five successive treatment days. These data demonstrate rapid and substantial diminution of the supersensitivity of the denervated dopamine D1 receptor following treatment with l-dopa + carbidopa or with a selective dopamine D1 agonist, while normosensitive dopamine D1 receptor-mediated locomotion in non-lesioned rats is unaltered.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

Evidence for involvement of both D1 and D2 receptors in maintaining cocaine self-administration.

Rats trained to self-administer cocaine (0.75 mg/kg/infusion) on an FR-5 schedule were treated with selective D1 or D2 antagonists. A69045, a D1 antagonist with no appreciable affinity for 5-HT receptors increased cocaine self-administration to 147, 172 and 167% of baseline at doses of 2.5, 5.0 or 10.0 mumol/kg, SC respectively. SCH-23390 (0.007, 0.015 and 0.030 mumol/kg, SC) increased self-administration to 116, 147 and 165% of baseline, respectively. Both D1 antagonists decreased responding in some animals at the highest dose tested. The D2 antagonist YM-09151-2 showed a similar profile, increasing cocaine self-administration at 0.01 and 0.016 mumol/kg, SC and suppressing responding by most animals at the dose of 0.03 mumol/kg, SC. These data give further support to the hypothesis that both D1 and D2 receptors are involved in maintaining cocaine self-administration.

Animals↗
PubMed1991

Synthesis and dopaminergic activity of 3-substituted 1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyrans: characterization of an auxiliary binding region in the D1 receptor.

The synthesis and dopaminergic activity of a series of C3 and nitrogen-substituted 1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyrans (isochromans) is described. The synthesis of the compounds was stereospecific for the 1,3 cis isomer, and the enantioselective synthesis of both enantiomers of one of the analogues (20) was achieved. It was determined that all of the dopaminergic activity resides in the [1R,3S] isomer. Generally, substitution at the C3 position provided compounds with very high potency (less than 10 nm EC50) and selectivity for the D1 receptor, with a wide range of intrinsic activities (60-160%). Analogues containing C3 substituents including aryl, arylalkyl, and cyclic and acyclic alkyl groups showed a marked enhancement of dopaminergic activity compared to the unsubstituted compound. As a class, the drugs were orally active in the rat rotation model with a very long duration of action.

Adenylyl Cyclases↗
PubMed1991

Synthesis and pharmacological evaluation of 1-(aminomethyl)-3,4-dihydro-5-hydroxy-1H-2-benzopyrans as dopamine D1 selective ligands.

A series of 3-substituted 1-(aminomethyl)-3,4-dihydro-5-hydroxy-1H-2- benzopyrans were prepared as potential D1 selective antagonists. The compounds were evaluated for their affinity and selectivity for the D1 receptor as well as for their functional antagonism of D1-mediated pharmacological events. The compounds show potent D1 antagonist properties in vitro. The optimum nitrogen substitution was found to be the primary amine and the observed order of potency for substitution at the 6-position is OH greater than Br greater than H greater than OMe. Two representative compounds, the 6-methyl and 6-bromo analogues, were also evaluated in vivo for dopaminergic activity. Interestingly, both compounds behave as potent in vivo agonists.

Adenylyl Cyclase Inhibitors↗
PubMed1991

Activation of the 5-HT1C receptor expressed in Xenopus oocytes by the benzazepines SCH 23390 and SKF 38393.

1. A cloned 5-HT1C receptor expressed in Xenopus laevis oocytes was used to characterize the action of four dopamine D1-selective benzazepines at the 5-HT1C receptor. Additionally, the apparent binding of the D1-selective benzazepines to 5-HT1C receptors was measured in the choroid plexus of the pig. 2. In voltage-clamped oocytes expressing the cloned 5-HT1C receptor, 5-hydroxytryptamine (5-HT) elicited a characteristic inward current response with an EC50 of 13 nM. SCH 23390 acted as a stereoselective agonist (or partial agonist) with an EC50 of about 550 nM. SKF 38393 (1 microM-1 mM), SKF 77434 (100 microM), and SKF 82958 (100 microM) also acted as agonists (or partial agonists) at the cloned 5-HT1C receptor. SKF 38393 was not stereoselective at the 5-HT1C receptor. 3. The response to SCH 23390 activated slowly and, although the response contained many oscillations characteristic of the activation of the phosphatidylinositol signal transduction system, SCH 23390 rarely elicited the rapid spike-like response seen routinely in response to 5-HT. However, the responses to SKF 38393, SKF 77434, and SKF 82958 were identical in appearance to the response to 5-HT, except that the responses to the benzazepines were smaller. These comparisons were made by applying both a benzazepine and 5-HT to each individual oocyte expressing the cloned 5-HT1C receptor. 4. Consistent with the responses measured in oocytes, SCH 23390 bound stereoselectively to 5-HT1C receptors in the choroid plexus of the pig (Ki = 6.3 nM), and SKF 38393 bound non-stereoselectively with lower affinity (Ki = 2.0-2.2 microM).5. It is concluded that while these benzazepines demonstrate selectivity for the dopamine D1 receptor, they also can act as agonists or partial agonists at the 5-HT1c receptor in situ and as expressed in Xenopus oocytes. The oocyte expression system is useful for studies of the functional pharmacology of these 5-HTic receptors. Information about the pharmacological actions and variations in stereoselectivity among dopamine and 5-HT receptors should be of interest in modelling the interactions of ligands with these G-protein coupled receptors, and in the testing of such models through receptor mutagenesis.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

A68930: a potent and specific agonist for the D-1 dopamine receptor.

A68930 (5,6-dihydroxy-3-phenyl-1-aminomethyl-isochroman) is a potent (EC50 = 2.5 nmol/L) partial agonist at the D-1 dopamine receptor. In contrast, A68930 is a much weaker agonist (EC50 = 3,920 nmol/L) at the D-2 dopamine receptor. The orientation of the 3-phenyl substituent in the molecule is critical for the affinity and selectivity of the molecule towards the D-1 receptor in vitro and in vivo. The role of the D-1 receptor in the functioning of the basal ganglia is discussed.

Animals↗
PubMed1989

A-69024: a non-benzazepine antagonist with selectivity for the dopamine D-1 receptor.

A-69024 HBr, 1-(2-bromo-4,5-dimethoxybenzyl)-7-hydroxy-6-methoxy-2-methyl-1,2,3,4- tetrahydroisoquinoline hydrobromide, is a selective antagonist of the dopamine D-1 receptor. A-69024 HBr shows an apparent affinity toward the D-1 receptor (identified using [125I]SCH 23390) of 12.6 (4.15-38.3) nM (mean (90% CL), n = 3); the apparent affinity toward the D-2 receptor (identified using [3H]spiroperidol is 1 290 (1,200-1,380) nM (n = 3); using [125I]lysergic acid diethylamine to identify the 5-HT1C receptor gives apparent affinity of 17,800 (9,700-32,600) nM (n = 3). In assays of adenylate cyclase activity, A-69024 HBr antagonizes the D-1 receptor with a calculated affinity of 43.9 (17.5-110) nM (n = 5), while the molecule antagonizes the D-2 receptor with a calculated affinity greater than 400 nM. Behavioral studies demonstrate that A-69024 HBr (5 mg/kg s.c.) is able to block both amphetamine-induced locomotor activity and apomorphine-induced stereotypy. Furthermore, A-69024 HBr blocks SF&F 38393-, but not quinpirole-, induced rotation in rats having unilateral 6-hydroxydopamine lesions of the substantia nigra. When administered at behaviorally effective doses. A-69024 HBr neither increases the concentration of serum prolactin nor potentiates dihydroxyphenylalanine (DOPA) accumulation in the caudate-putamen of rats pretreated with the DOPA decarboxylase inhibitor NSD 1015. Because A-69024 is a dopamine receptor antagonist discriminating between the D-1 and D-2 receptors, it may be a useful research tool.

Adenylyl Cyclases↗
PubMed1986

D-2 dopaminergic agonists and adenosine 3',5'-monophosphate directly regulate the synthesis of alpha-melanocyte-stimulating hormone-like peptides by cultured rat melanotrophs.

When placed in short term (2-day) tissue culture, the melanotrophs from the intermediate lobe of the rat pituitary gland synthesize a proopiomelanocortin-like material (POMC-LM). Exposure of these cells to bromocriptine (CB 154), an agonist upon their D-2 dopamine receptor, reduces the synthesis of POMC-LM; spiroperidol, an antagonist of the D-2 receptor, prevents this effect of CB 154. Cultured melanotrophs secrete an alpha MSH-like material. The amount of this alpha MSH-like material, either stored intracellularly or secreted into the culture medium, can be quantified in a specific RIA; the material identified in this manner is designated immunoreactive alpha MSH (IR-alpha MSH). CB 154 inhibits the secretion of IR-alpha MSH from these cells. Either spiroperidol or 8-bromo-cAMP prevent this inhibitory effect of CB 154. The capacity of these cells to synthesize alpha MSH-like molecules and release them into the culture medium can be assessed by incubation in the presence of [3H]tyrosine, followed by immunoprecipitation with an antibody directed against alpha MSH. This newly synthesized immunoprecipitable material is designated immunoprecipitable alpha MSH (IP-alpha MSH) and should be distinguished from IR-alpha MSH. Both CB 154 and quinpirole, a selective D-2 agonist (but not SKF 38393, a selective D-1 agonist), inhibit the synthesis and secretion of IP-alpha MSH. YM-09151-2, a selective D-2 antagonist (but not SCH 23390, a selective D-1 antagonist), blocks the inhibitory effects of quinpirole. Several compounds affecting cAMP metabolism (cholera toxin, forskolin, 8-bromo-cAMP, and 3-isobutyl-1-methylxanthine) can also prevent the inhibitory effect of CB 154 on the synthesis of IP-alpha MSH. We conclude the following. The D-2 receptor in the intermediate lobe directly regulates the synthesis and secretion of IP-alpha MSH. cAMP can regulate either the synthesis of POMC-LM or the processing of this substance into alpha MSH-like peptides.

1-Methyl-3-isobutylxanthine↗