摘要:

AbstractPeptide receptors represent important targets for a variety of potentially important disease modifying drugs. Over the past 20 years, considerable effort has been spent on modifying the natural ligands for peptide receptors, the peptides themselves, with limited success. Using a targeted screen, namely cholecystokinin (CCK)‐A receptor binding, the Merck group in 1984 discovered asperlicin, a potent non‐peptide cholecystokinin antagonist selective for peripheral tissues, that was isolated fromAspergillus alliaceaus. This compound was used as a lead to develop MK‐329, a CCK‐A receptor antagonist, the evolution of which is discussed within the context of the drug discovery process and receptor modeling strategies. © 1993 Wiley

ISSN:0272-4391    

DOI:10.1002/ddr.430290402

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractThe enhancement of acetylcholine (ACh) release during electrical or potassium depolarization was compared in the presence of either linopirdine or 4‐aminopyridine (4‐AP) using two different functional assays. We measured ACh and choline (Ch) directly from striatal perfusates using high performance liquid chromatography and electrochemical detection or indirectly by measuring ACh‐mediated twitch height changes in the electrically stimulated guinea pig ileum. Potassium‐induced twitch responses were also measured in resting ileal segments. Linopirdine significantly enhanced ACh release in the presence of elevated potassium levels in rat striatal slices and guinea pig ileum, but had no effect during electrical stimulation in either model. In contrast, 4‐AP enhanced ACh release in both electrically stimulated striatal slices and ileal strips. In agreement with other studies, atropine enhanced ACh release during either electrical or potassium stimulation paradigms in the striatal slice. The in vitro observations in this report suggest that linopirdine has limited ability to augment the cholinergic neurotransmission evoked by electrical stimulation. © 1993 Wiley

ISSN:0272-4391    

DOI:10.1002/ddr.430290403

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractIt has recently been shown that the increase in external carotid blood flow (external CBF) produced by 5‐hydroxytryptamine (5‐HT) in the anaesthetized dog, being mimicked by 5‐carboxamidotryptamine, potently blocked by methiothepin and resistant to blockade by ritanserin and MDL 72222, is mediated by 5‐HT1‐like receptors. In the present investigation, we have further characterized these 5‐HT1‐like receptors. Like 5‐HT, 1 min intracarotid (i.c.) infusions of the 5‐HT1Areceptor agonist, indorenate, produced an increase in external CBF without modifying mean arterial blood pressure or heart rate. Contrasting with indorenate, 1 min i.c. infusions of the 5‐HT1Areceptor agonists, 8‐hydroxy‐2(di‐N‐propylamino)tetralin (8‐OH‐DPAT), buspirone and ipsapirone, or the 5‐HT1A/5‐HT1Breceptor agonist, 5‐methoxy‐3‐[1,2,3,6‐tetrahydro‐4‐pyridinyl]‐1‐H‐indol succinate (RU 24969), resulted in dose‐dependent decreases in external CBF; furthermore, both the 5‐HT1C/5‐HT2receptor agonist, 1‐(2,5‐dimethoxy‐4‐iodophenyl‐)‐aminopropane (DOI) and the 5‐HT3receptor agonist, 2‐methyl‐5‐hydroxytryptamine (2‐methyl‐5‐HT), were essentially inactive. Thus, only indorenate increased the external CBF in the dog; this effect of indorenate was not antagonized by intravenous (i.v.) administration of the 5‐HT1and 5‐HT2receptor antagonist, methiothepin, or completely abolished after sympathectomy. Unlike methiothepin, the 5‐HT1Aand 5‐HT1Breceptor antagonist, (±)‐pindolol, did not block indorenate‐induced external carotid vasodilatation. Together, the above results support the notion that indorenate is acting on the 5‐HT1‐like receptors involved in the increase in external CBF in the dog. These receptors, which are probably located on carotid sympathetic nerve endings,

ISSN:0272-4391    

DOI:10.1002/ddr.430290404

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractIn search of antiglaucoma agents which can increase the ocular blood flow and effectively lower the intraocular pressure (IOP), numerous antiglaucoma drugs were investigated to determine their ability to increase the ocular pulsatile blood flow in ocular hypertensive rabbits with the intraocular pressure artificially raised to 40 mmHg. It was found that various antiglaucoma drugs increased ocular pulsatile flow; these included (with percent increase) ethoxzolamine (36–56%), pilocarpine (65%), physostigmine (43–83%), echothiophate (23–62%), timolol (28–42%), levobunolol (37–55%), betaxolol (35%), and epinephrine (61%). Metipranolol, metoprolol, and clonidine had no effect on pulsatile blood flow. These results indicate that most antiglaucoma drugs, with the exception of a few, can enhance the ocular pulsatile blood flow in ocular hypertensive rabbits. © 1993 Wiley

ISSN:0272-4391    

DOI:10.1002/ddr.430290405

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractThe effects of chronic theophylline treatment on brain adenosine A1receptors and amygdala‐kindled seizures were examined in rats. The repeated administration of theophylline 417 μmoles/kg/day i.p. (75 mg/kg/day) for 14 days resulted in a significant increase in 1 nM [3H]cyclohexyladenosine binding to adenosine A1receptors in thalamus, hippocampus, and cerebellum. This chronic theophylline treatment was shown to significantly prolong the immediate postseizure refractory period (defined as sensitivity to a subsequent kindling stimulation) while both the severity and duration of an initial kindled seizure was not affected. These findings indicate that the postseizure refractory period can be influenced by the brain adenosine system, and implicate adenosine as an important neuromodulator of the patterning of seizure episodes. © 1993 Wiley‐Liss

ISSN:0272-4391    

DOI:10.1002/ddr.430290406

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

Abstract8‐(3‐Isothiocyanatostyryl)caffeine (ISC) was synthesized and shown to inhibit selectively the binding of [3H]CGS 21680 (an A2a‐selective agonist) at adenosine receptors in striatal membranes. The Kivalue at A2a‐receptors was found to be 110 nM (rat), with selectivity ratios for A2aversus A1‐receptors in rat, guinea pig, bovine, and rabbit striatum of>100‐fold. Preincubation of membranes with ISC caused a dose‐dependent, irreversible antagonism of the binding of [3H]CGS 21680, with an IC50value of 3 μM. The irreversibility is likely due to the presence of the chemically reactive isothiocyanate group, since the binding of the corresponding analogue in which the isothiocyanate was replaced with a chloro group was completely reversible. The potency of ISC to irreversibly inhibit the binding of [3H]CGS 21680 in several species varied in the order rat ≈︁ guinea pig>bovine ≈︁ rabbit. In all four species, binding of the A1‐selective agonist [3H]R‐N6‐phenylisopropyladenosine was not diminished by pre‐treatment with 2 μM ISC. The kinetics of irreversible inhibition of rat A2a‐receptors by 2 μM ISC gave a t1/2of approximately 3 min. Following partial inactivation, the remaining rat A2a‐binding sites retained the same Kdvalue as in control membranes for saturatin by [3H]CGS 21680. Thus, ISC appears to be a selective affinity label for A2a‐ versus A1‐recept

ISSN:0272-4391    

DOI:10.1002/ddr.430290407

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractThe analgesic effects of combinations of either aspirin or acetaminophen with morphine, d‐propoxyphene, and pentazocine were studied in the pain‐induced functional impairment in the rat model (PIFIR). Pain was induced by the intra‐articular injection of uric acid in the right hind limb inducing its dysfunction. Animals then received analgesic agents, and the recovery of functionality over time was assessed as an expression of analgesia. The combination of aspirin with either morphine or d‐propoxyphene resulted in analgesic effects similar to those expected on the basis of addition of the effects of the individual component drugs. However, the combination of aspirin with either morphine or d‐propoxyphene resulted in analgesic effects similar to those expected on the basis of addition of the effects of the individual component drugs. However, the combination of aspirin and pentazocine resulted in a potentiation (46%), the observed analgesia being significantly greater than the expected effect. Coadministration of acetaminophen and morphine resulted in an analgesic effect that was not different from that expected on the basis of addition, whereas acetaminophen with d‐propoxyphene resulted in a lower effect (21%). Moreover, the combination of acetaminophen and pentazocine resulted in a lower effect (21%). Moreover, the combination of acetaminophen and pentazocine resulted in an effect that was similar to that seen with either acetaminophen or pentazocine alone. The percent change in combination was 41% lower than the addition of the individual effects. It appears that, while certain combinations of opioids and nonsteroidal anti‐inflammatory drugs (NSAIDs) may be beneficial, other combinations may be detrimental. Therefore, great care should be taken in the choice of the components of analgesic drug mixtures. Preclinical pharmacological information about the efficacy of drug associations should be taken into consideration before testing in humans. © 1993 W

ISSN:0272-4391    

DOI:10.1002/ddr.430290408

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractThe ability of [3H]5′‐N‐ethylcarboxamidoadenosine (NECA) to specifically bind recognition sites on intact Chinese hamster ovary (CHO) cells was examined in the present study. Saturation experiments indicated that [3H]NECA bound with moderate affinity (Kd = 400 nM) and large capacity (apparent Bmax = 3.2 pmol/105cells) to intact CHO cells. No specific binding to these cells was observed with the A1‐selective agonist 20 nM [3H]cyclohexyladenosine or with the A2‐selective agonist 20 nM [3H]CGS 21680. Competition studies revealed that close structural analogs of NECA and the xanthine phosphodiesterase inhibitor 3‐isobutyl‐1‐methylxanthine (IBMX) inhibited 20 nM [3H]NECA binding with moderate affinity (IC50s 0.5–15 μM). Adenosine also showed weak activity (IC50= 100 μM) for inhibiting [3H]NECA binding. However, a wide variety of prototypic adenosine receptor agonists and antagonists did not significantly interact with these [3H]NECA recognition sites on CHO cells. [3H]NECA binding to CHO cell membranes was not sensitive to guanine nucleotides and NECA did not stimulate cAMP formation. These results are consistent with the previously demonstrated ability of [3H]NECA to bind low affinity adenosine binding proteins (adenotin proteins), as well as, adenosine receptors in a variety of mammalian tissues. The present results further indicate that [3H]NECA selectively labels in adenotin‐like recognition site on intact CHO cells in the absence of detectable binding to high affinity adenosine receptors.

ISSN:0272-4391    

DOI:10.1002/ddr.430290409

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430290410

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430290401

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY