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A A Hancock

Publications and source records attributed to A A Hancock.

At least 37 records · Page 2Linked to original sources
PubMed2003

Molecular modeling and pharmacological analysis of species-related histamine H(3) receptor heterogeneity.

Presynaptic histamine H(3) receptors (H(3)R) regulate neurotransmitter release in the central nervous system, suggesting an important role for H(3) ligands in human diseases such as cognitive disorders, sleep disturbances, epilepsy, or obesity. Drug development for many of these human diseases relies upon rodent-based models. Although there is significant sequence homology between the human and rat H(3)Rs, some compounds show distinct affinity profiles. To identify the amino acids responsible for these species disparities, various mutant receptors were generated and their pharmacology studied. The N-terminal portion was shown to determine the species differences in ligand binding since a chimeric H(3)R containing N-terminal human and C-terminal rat receptor sequences exhibited similar pharmacology to the human receptor. Sequence analysis and molecular modeling studies suggested key amino acids at positions 119 and 122 in transmembrane region 3 play important roles in ligand recognition. Mutant receptors changing amino acids 119 or 122 of the human receptor to those in the rat improved ligand binding affinities and functional potencies of antagonist ligands, confirming the significant role that these amino acids play in species-related pharmacological differences. A model has been developed to elucidate the ligand receptor interactions for H(3)Rs, and pharmacological aspects of this model are described.

Amino Acid Sequence↗
PubMed2001

Species-related pharmacological heterogeneity of histamine H(3) receptors.

We compared radioligand binding and functional data for histamine H(3) receptor ligands across different tissues or species to evaluate the basis for pharmacological evidence of receptor heterogeneity previously reported. Agonist binding affinities showed correlation coefficients near unity in comparing human, dog, rat, and guinea pig cerebral cortical histamine H(3) receptors. Antagonist binding affinities revealed lower correlations for human compared to dog, rat, or guinea pig, suggesting species-based pharmacological differences. The functional potencies of histamine H(3) receptor antagonists in field-stimulated guinea pig ileum were highly correlated to binding affinities for guinea pig, dog, and, to a lesser extent, rat cerebral cortex. However, antagonist binding affinity at human cerebral cortex did not correlate well with guinea pig ileum functional potency. These results suggest significant interspecies histamine H(3) receptor heterogeneity, consistent with recent receptor gene sequence data. Therefore, genetic heterogeneity, rather than peripheral and central histamine H(3) receptor diversity, is responsible for the pharmacological differences observed.

Animals↗
PubMed2001

Structure-activity studies for a novel series of bicyclic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia.

In search of a uroselective alpha1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,(1) this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the alpha1A/alpha1B selectivity of these compounds were identified. In vitro functional assays for the alpha1 adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2001

Comparison of alpha 1-adrenoceptor agonists in canine urethral pressure profilometry and abdominal leak point pressure models.

PURPOSE: We describe and compare the usefulness of 3 minimally invasive dog urethral function models to demonstrate the efficacy potential of alpha 1 agonists for stress urinary incontinence. From this overall composite dataset the efficacy profiles of the alpha 1A selective agonist A-61603 and the active metabolite of midodrine ST-1059 were specifically compared. MATERIALS AND METHODS: Isoflurane anesthetized multiparous female beagle dogs were used in all studies. Intraurethral pressure was measured using a 7Fr balloon catheter. Profilometry was performed using an 8Fr Millar transducer catheter. Bladder pressure required to produce leakage in response to external abdominal ballottements of increasing intensity was measured using a 5Fr transurethral catheter. Agonist responses were measured before and after increasing cumulative intravenous doses of each compound in each test. RESULTS: Agonist induced increases in maximal urethral closure and leak point pressure strongly correlated in linear fashion (R(2) = 0.94), as did measurements of agonist induced increases in proximal intraurethral pressure using the microtransducer or balloon catheter technique (R(2) = 0.87). A dose of 0.01 to 1 nmol./kg. A-61603 and 10 to 1,000 nmol./kg. ST-1059 intravenously each caused dose dependent increases in maximum urethral closure, leak point and intraurethral pressure. CONCLUSIONS: While the dose range for which alpha 1 agonists affect urethral pressure was adequately predicted by any of the 3 methods used, the leak point pressure assay described has the advantage of being a dynamic test that directly evaluates efficacy to protect against leakage caused by increases in abdominal pressure. This leak point pressure test appears be useful for the preclinical evaluation of compounds used to treat stress urinary incontinence.

Adrenergic alpha-1 Receptor Agonists↗
PubMed2000

Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole alpha(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH).

In search of a uroselective agent that exhibits a high level of selectivity for the alpha(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the alpha(1) adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.

Adrenergic alpha-Antagonists↗
PubMed1998

Cardiovascular activity of A-74283, a 5-hydroxytryptamine 1A agent, in the spontaneously hypertensive rat.

A-74283, (+,-)trans-2-(4-(3a,4,4a,6a,7,7a-hexahydro-4,7-etheno-1 H cyclobut [f] isoindol-1,3-dionyl)-butyl)-9-methoxy-2,2,2a,4,5,9b-hexahydr o-1 H-benz[e]isoindol HC1, was studied in receptor binding assays and in the spontaneously hypertensive rat (SHR). In radioligand binding to rat cortex, A-74283 had high affinity (equipotent to 8-OH-DPAT) and high selectivity for 5HT1A receptors compared to 5HT1B sites. In conscious SHR, A-74283 lowered mean arterial pressure (MAP) in a dose-related fashion with a prolonged effect after oral administration of higher doses, but heart rate (HR) was not changed. In anesthetized SHR, i.v. administration of A-74283 decreased MAP and total peripheral resistance, but not cardiac output. Pretreatment of conscious SHR with the selective 5TH1A receptor antagonists spiroxatrine or BMY 7378 reduced the hypotensive effect of A-74283 significantly, but pretreatment with adrenergic antagonists phenoxybenzamine or idazoxan or the 5HT2 receptor blocker ketanserin did not alter the effect of A-74283. Intracisternal administration of A-74283 also decreased MAP; however, A-74283 had no effect on blood pressure in pithed SHR in which blood pressure was supported with vasopressin, in contrast to nitroprusside. These data demonstrate that A-74283 exerts a potent hypotensive effect in SHR via systemic vasodilation originating from a central 5HT1A receptor mechanism. A-74283 may be useful for studying 5HT1A receptors and cardiovascular function.

Adrenergic Antagonists↗
PubMed1998

Histaminergic ligands attenuate barrel rotation in rats following unilateral labyrinthectomy.

In this paper we present a unilateral labyrinthectomy (UL) surgical procedure in rats that was derived from previous techniques. The utility of this model to assess vestibular dysfunction was evaluated by examining the ability of clinically used histaminergic agents and more selective H3 receptor antagonists to attenuate of UL-induced body rotations. Unilateral labyrinthectomy was performed by injection of ethanol into the rat right inner ear. An elevated body rotation test (EBRT) was used to assess the abnormal rotational behavior induced by UL. Scores of "3" to "0" were used to characterize the degree of abnormal behavior according to the latency of body rotations to begin. Our results demonstrate that: i) 100 microliters ethanol induced robust behavioral changes, which was used in further experiments; ii) the clinically used antivertigo agent, astemizole, significantly reduced the rotational behavior in UL rats; iii) the more potent H3 antagonists, thioperamide and GT-2016, were more efficacious than betahistine, a mixed H3 antagonist and H1 agonist. These results indicate that this model may be a potential tool for testing novel drugs for antivertigo effects and provide better support to the role of the histaminergic system in the control of vestibular function.

Animals↗
PubMed1998

Actions of A-131701, a novel, selective antagonist for alpha-1A compared with alpha-1B adrenoceptors on intraurethral and blood pressure responses in conscious dogs and a pharmacodynamic assessment of in vivo prostatic selectivity.

A-131701 (3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b, hexahydro-[1H]-benz[e]isoindol-2-yl)ethyl]pyrido [3',4': 4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione) is a novel compound previously shown to be selective for alpha-1a sites compared with alpha-1b adrenoceptors in radioligand binding studies and isolated tissue bioassays and to block canine urethral pressure (IUP) responses to exogenous alpha-1 adrenergic agonists to a greater extent than blood pressure responses. In conscious dogs in which IUP and mean arterial blood pressure (MABP) responses were measured periodically up to 24 hr, A-131701 blocked phenylephrine (PHE)-induced increases in IUP to a greater extent than MABP responses, and the blockade of the IUP effects of PHE was significantly different from control for up to 12 hr after doses greater than 0.3 mg/kg p.o., whereas blood pressure effects were of a lesser extent and duration. In addition to the weak antagonism of PHE-induced blood pressure responses, A-131701 also exhibited minimal effects on basal blood pressure in the dog, unlike terazosin, doxazosin or tamsulosin. Pharmacokinetic analysis of plasma samples from dogs indicated that A-131701 had a half-life of 0.4 to 0.8 hr and a bioavailability of 30 to 50% in dogs. Somewhat longer half-lives were observed in rat and monkey, with bioavailability values in the 25 to 30% range. Evidence of nonlinearity of pharmacokinetics was obtained in dogs and monkeys. Pharmacodynamic analysis revealed differences between A-131701 and nonselective alpha-1 adrenoceptor antagonists in selectivity for prostatic versus vascular alpha-1 adrenoceptors based on either extent or duration of blockade, which were either similar to or superior to compounds such as tamsulosin or REC 15/2739. These data demonstrate that A-131701 selectively blocks canine prostatic alpha-1 adrenoceptors for prolonged periods compared with MABP responses in vivo. Therefore, A-131701 should have clinical utility in the pharmacotherapy of benign prostatic hyperplasia.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1997

[3H]R-terazosin binds selectively to alpha1-adrenoceptors over alpha2-adrenoceptors - comparison with racemic [3H]terazosin and [3H]prazosin.

Most tissue sources for adrenoceptors contain a mixed population of alpha1- and/or alpha2-adrenoceptor subtypes; thus studies using non-specific radioligands are complicated by receptor heterogeneity. The examination of alpha1-adrenoceptor radioligand binding by radiolabeled terazosin and its enantiomers was simplified by using mouse fibroblast cells, which are thymidine kinase mutant (LTK-), transfected with cloned alpha1a-, alpha1b-, and alpha1d-adrenoceptor subtypes. [3H]Terazosin and its enantiomers were equipotent at the alpha1b-adrenoceptor. [3H]R-Terazosin was significantly less potent than [3H]terazosin and [3H]S-terazosin at the alpha1a- and the alpha1d-adrenoceptors. Using tissue derived alpha-adrenoceptors prepared in cold 25 mM glycyl-glycine buffer, [3H]prazosin, [3H]terazosin and [3H]S-terazosin bound to two sites in the rat neonatal lung preparation consistent with the presence of both alpha1- and alpha2B-adrenoceptors. The relative binding potencies of these radioligands at these two sites correlated with low affinity binding to the alpha2B-adrenoceptor and high affinity binding to an alpha1-adrenoceptor. [3H]R-Terazosin, on the other hand, bound to a single site in the rat neonatal lung membrane preparation, most likely an alpha1-adrenoceptor. Thus, [3H]R-terazosin may be useful as a selective alpha1-adrenoceptor radioligand for establishing the functional role of adrenoceptors in tissues expressing multiple subtypes.

Adrenergic alpha-Antagonists↗
PubMed1997

Structure-activity studies for a novel series of N-(arylethyl)-N-(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamine s possessing dual 5-HT uptake inhibiting and alpha2-antagonistic activities.

In search of an alpha2-antagonist/5-HT uptake inhibitor as a potential new class of antidepressant with a more rapid onset of action, compound 3 was prepared and observed to possess high affinity for the alpha2-receptor (K(i) = 6.71 nM) and the 5-HT uptake site (20.6 nM). A series of tertiary amine analogs of 3 were synthesized and assayed for their affinity at both the alpha2-receptor and the 5-HT uptake site. The structure-activity relationship reveals that a variety of structural modifications to the arylethyl fragment are possible with retention of this dual activity. On the tetralin portion, 5-OMe substitution and the (R) stereochemistry at C-1 are optimal with alternate substitutions producing compounds retaining high affinity for the alpha2-receptor but lacking affinity for the 5-HT uptake site. Data for several rigidified 5-O-alkyl analogs suggests that the favored orientation of the oxygen lone pairs may be away from the 6-position of the tetralin.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1997

Relationships between pharmacokinetics and blockade of agonist-induced prostatic intraurethral pressure and mean arterial pressure in the conscious dog after single and repeated daily oral administration of terazosin.

The purpose of this study was to determine the potency and selectivity of the alpha-1 adrenergic receptor antagonist terazosin based on relationships between plasma concentrations and blockade of intraurethral pressure (IUP) and mean arterial pressure (MAP) responses after single dosing and to determine cumulative effects after repeated dosing. To this end, the relationships between plasma concentrations and blockade effects of terazosin on phenylephrine (PE)-induced IUP and MAP were evaluated in conscious male beagle dogs after single (0.1, 0.3 and 1 mg/kg) and repeated (0.3 and 1 mg/kg) daily oral dosing of terazosin. Blockade effects and plasma concentrations were evaluated at selected times for periods of < or = 24 hr. Terazosin produced dose-dependent antagonism of PE-induced IUP and MAP responses. When IUP and MAP blockade effects were plotted against terazosin plasma concentration, direct relationships were observed that were well described by the sigmoidal maximal effect model and resulted in IUP and MAP IC50 values of 48.6 and 12.2 ng/ml, respectively. Repeated daily dosing resulted in little accumulation of terazosin in plasma and demonstrated consistent blockade responses over 7 days. MAP blockade was observed up to 23 hr after terazosin administration, whereas IUP blockade returned to control levels before 23 hr. Combined pharmacokinetic/pharmacodynamic analysis showed no selective antagonism of IUP by terazosin but may provide a useful way to show uroselectivity of novel agents.

Administration, Oral↗
PubMed1996

Synthesis and in vitro characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers: a novel selective alpha 1A receptor agonist.

The existence of multiple subtypes of the alpha 1 adrenergic receptor has been demonstrated both pharmacologically and by molecular biological cloning techniques. The development of subtype selective antagonists has been the focus of much research within the pharmaceutical industry, and clinical evidence now exists that alpha-1A selective antagonists will have utility in the treatment of benign prostatic hyperplasia. However, highly subtype selective agonists are not known. Herein we report the synthesis and pharmacological characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers, a highly potent full agonist with excellent selectivity for the alpha 1A receptor subtype.

Adrenergic alpha-Agonists↗
PubMed1996

Alpha 1-adrenoceptor-induced contractility in rat aorta is mediated by the alpha 1D subtype.

Adrenoceptor agonists were used to characterize the alpha 1-adrenoceptor subtype responsible for mediating tension (phasic and tonic combined) in the denuded rat aorta and compared with radioligand binding at alpha 1-adrenoceptor subtypes. The rank order of potency at the rat aorta was the same as that obtained for binding affinity at the rat clonal alpha 1d-adrenoceptor: norepinephrine > epinephrine > cirazoline > phenylephrine > oxymetazoline > A-61603 > methoxamine. Correlation coefficients comparing rat aortic contraction (pD2) to binding (pKi) were 0.09-0.21 for alpha 1A/a receptors, 0.66 for clonal alpha 1b and 0.94 for clonal alpha 1d-adrenoceptors. Correlation coefficients comparing the clonal alpha 1d-adrenoceptor binding affinity to in vitro contractile responses were 0.03 and 0.10 for the rat vas deferens and canine prostate alpha 1A-adrenoceptor responses, respectively, 0.09 for the rat spleen alpha 1B and as noted, 0.94 for the rat aorta. The agreement observed between agonist potency at the rat aorta and affinity for the alpha 1d binding site provide new evidence that the alpha 1D-adrenoceptor subtype is responsible for mediating contractions in the rat aorta.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1996

Effects of selective and nonselective alpha-1-adrenoceptor antagonists on intraurethral and arterial pressures in intact conscious dogs.

In this study, we used a novel conscious dog model to evaluate the uroselectivity of selected alpha 1-antagonists either approved for human use or in clinical development for the treatment of symptomatic benign prostatic hyperplasia (BPH) and compared those results to their in vitro binding and functional affinities at alpha 1A, alpha 1B and alpha 1D receptor subtypes. Conscious dogs were instrumented acutely with a balloon catheter for the measurement of changes in prostatic intraurethral pressure (IUP) and chronically with implantable telemetry devices for the measurement of arterial pressure. The pressor effects of the alpha 1-agonist phenylephrine (PE) on IUP and mean arterial pressure (MAP) were compared before and at various time points after oral doses of either terazosin, doxazosin, tamsulosin or Rec 15/2739 (SB 216469). At submaximal doses, terazosin and doxazosin blocked PE-induced increases in MAP to a greater extent than increases in IUP. Tamsulosin blocked both parameters equally at the lowest and highest doses; however, at the intermediate dose, IUP was blocked more than MAP. Rec 15/2739 at each dose always blocked IUP to a greater extent than MAP. While the in vivo uroselectivity of these agents was predicted by radioligand binding and in vitro functional selectivity for the alpha 1A subtype over alpha 1B and alpha 1D subtypes, results from conscious dog experiments indicate that estimates of in vivo uroselectivity also depend upon dose and the time after administration. Our conscious canine model provides the basis for frequent and repeated evaluation of uroselectivity parameters over many hours, thus providing a pharmacological profile of compound effects perhaps more relevant to clinical practice.

Adrenergic alpha-Antagonists↗
PubMed1996

Pharmacologic characterization of CHIR 2279, an N-substituted glycine peptoid with high-affinity binding for alpha 1-adrenoceptors.

We characterize the in vitro and in vivo pharmacology of CHIR 2279, an N-substituted glycine peptoid previously identified from a combinatorial library as a novel ligand to alpha 1-adrenoceptors. Competitive receptor-binding assays with [3H]prazosin showed that CHIR 2279 was similar to prazosin in binding to alpha 1A (rat submaxillary), alpha 1a, alpha 1b, and alpha 1 d (cDNA expressed in LTK- cells) with high and approximately equipotent affinity. Ki values for CHIR 2279 ranged from 0.7 to 3 nM, and were 10-fold weaker than with prazosin. Functional assays for postsynaptic alpha 1-adrenoceptors showed CHIR 2279 was approximately equipotent in antagonizing agonist-induced contractile responses with rat was deferens (alpha 1A), canine prostate (alpha 1A), rat spleen (alpha 1B) and rat aorta (alpha 1D). The pA2 for CHIR 2279 averaged 7.07 in these assays, indicating a 10- to 100-fold lower in vitro potency than prazosin. In dogs, CHIR 2279 antagonized the epinephrine-induced increase in intraurethal pressure (pseudo pA2, 6.86) and in rats antagonized the phenylephrine-induced increase in mean arterial blood pressure. In rats and guinea pigs, CHIR 2279 induced a dose-dependent decrease in mean arterial blood pressure without eliciting the tachycardia commonly observed with other alpha 1-blockers. Pharmacokinetic/pharmacodynamic modeling showed the i.v. system clearance rate of CHIR 2279 was 60 and 104 ml/min/kg in rats and guinea pigs, respectively, and the in vivo potency for mean arterial blood pressure reduction was twice as great in guinea pigs (EC50, 520 ng/ml) than rats (EC50, 1170 ng/ml).

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1995

A-61603, a potent alpha 1-adrenergic receptor agonist, selective for the alpha 1A receptor subtype.

N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydro naphthalen-1-yl] methanesulfonamide hydrobromide (A-61603) is a novel and potent alpha-adrenoceptor agonist. In radioligand binding assays, the compound is at least 35-fold more potent at alpha 1A/a receptors than at alpha 1b or alpha 1d sites. In fibroblast cells transfected with alpha 1a receptors, A-61603 more potently stimulates phosphoinositide hydrolysis than norepinephrine, and is antagonized by prazosin. A-61603 is less potent in cells transfected with alpha 1b or alpha 1d receptors. A-61603 is a potent agonist at alpha 1A receptors in rat vas deferens (200- to 300-fold more potent than norepinephrine or phenylephrine, respectively) and in isolated canine prostate strips (130- to 165-fold more potent than norepinephrine or phenylephrine, respectively). In contrast, A-61603 is only 40-fold more potent than phenylephrine at alpha 1B sites in rat spleen and 35-fold less potent at rat aortic, alpha 1D sites. In an in vivo dog model, A-61603 raises intraurethral prostatic tone to a greater extent than mean arterial blood pressure. A-61603 induces a pressor response in conscious rats at doses 50- to 100-fold lower than phenylephrine, and the response is not attenuated by pretreatment with CEC, whereas YM-617 causes a 100-fold shift in the response. These results indicate that A-61603 is a potent adrenergic agonist, selective for alpha 1A/a receptors, and may prove a useful probe for studies of adrenergic function and alpha 1 adrenoceptor regulation of physiological functions.

Adrenergic alpha-1 Receptor Agonists↗