Membrane permeability related physicochemical properties of a novel gamma-secretase inhibitor

Pharmaceutical profiling studies were conducted on a novel prototype γ-secretase inhibitor, to determine the potential of its oral absorption. Such compounds can be of use in the treatment of Alzheimer’s disease (AD). The studies included determination of solubility, dissociation constant (pK_a), octanol/water partition coefficient (log P) and the capacity factor (k_IAM′) on immobilized artificial membrane (IAM) chromatographic columns. The compound is very slightly solubility in water (120 ± 50 μg/mL) but the solubility increased considerably in basic medium (270 ± 60 μg/mL). The compound exhibited pK_a of (10.36 ± 0.11); and log P of (3.36 ± 0.16) determined by shake-flask method and (3.31 ± 0.01) determined by high performance liquid chromatography (HPLC). The experimentally determined log P values correlated well with the calculated one of 3.44. The observed log k_IAM′ value of (2.79 ± 0.04) indicates that the compound can reasonably be expected to have high membrane permeability, and therefore, good absorption profile if taken orally. This conclusion is also supported by other parameters determined.     

Synthesis and alpha 2-adrenoceptor effects of substituted catecholimidazoline and catecholimidazole analogues in human platelets

It is known that the steric requirements for the interactions of catecholamines and catecholimidazolines with alpha 1- and alpha 2-adrenoceptors are different. New analogues of desoxycatecholimidazoline (1), desoxycatecholimidazole (3), benzylic hydroxyl substituted imidazole (4), and the aromatic fluorine substitution analogues of 1 at the 2 (5), 5 (6), and 6 (7) positions, and a set of asymmetric 4-substituted catecholimidazolines, S-8 and R-8, were prepared and tested for interaction with alpha 2-adrenoceptors in human platelets. With the exception of 3, all compounds were selective for alpha-adrenoceptor-mediated responses in human platelets. Introduction of a double bond in imidazoline 1 to give an imidazole 3 or the introduction of a benzylic hydroxyl group to 3, as in 4, reduced the inhibition of platelet aggregation with a rank order potency of 1 greater than 3 greater than 4. Fluorine atom substitution at the 2-, 5-, or 6-positions only slightly modified the inhibitory activity of 1. Each analogue (1, 3-7) produced alpha 2-mediated inhibition of platelet adenylate cyclase and can be classified as a partial agonist. The inhibition potency of S-8 and R-8 against epinephrine-induced aggregatory responses were greatly different, and only R-8 and 4 were alpha 2-agonists on human platelet function. Our studies provide further evidence for the differential interaction of catecholamines and catecholimidazolines in alpha 1- and alpha 2-adrenoceptor systems.     

Syntheses and analytical characterizations of N‐alkyl‐arylcyclohexylamines

The rise in new psychoactive substances that are available as 'research chemicals’ (RCs) remains a significant forensic and legislative challenge. A number of arylcyclohexylamines have attracted attention as RCs and continue to be encountered, including 3‐MeO‐PCP, 3‐MeO‐PCE and 3‐MeO‐PCPr. These compounds are commonly perceived as ketamine‐like dissociative substances and are believed to act predominantly via antagonism of the N‐methyl‐D‐aspartate (NMDA) receptor. To aid in the identification of newly emerging substances of abuse, the current studies were performed. The syntheses of fifteen N‐alkyl‐arylcyclohexylamines are described. Analytical characterizations were performed via gas chromatography and high performance liquid chromatography coupled to multiple forms of mass spectrometry as well as nuclear magnetic resonance spectroscopy, ultraviolet diode array detection and infrared spectroscopy. The series consisted of the N‐alkyl derivatives (N‐methyl, N‐ethyl, N‐propyl) of phenyl‐substituted and isomeric 2‐, 3‐ and 4‐methoxy phenylcyclohexylamines, as well as the N‐alkyl derivatives obtained from 3‐methylphenyl and 2‐thienyl moieties. In addition to the presentation of a range of previously unreported data, it was also found that positional isomers of aryl methoxyl‐substituted arylcyclohexylamines were readily distinguishable under a variety of analytical conditions. Copyright © 2015 John Wiley & Sons, Ltd.     

Activation of alpha-1 adrenoreceptors of rat aorta by analogs of imidazoline

New analogs of desoxycatecholimidazoline were synthesized for elucidating the steric requirements for the activation of alpha-1 adrenoreceptors. The compounds tested on rat thoracic aorta in this study were: desoxycatecholimidazole with and without bridge carbon hydroxyl group, analogs of desoxycatecholamidazoline with fluorine substitution at position 2, 5 or 6 of the catechol ring and hydroxybenzyl group at carbon-4 of the imidazoline part of the molecule. The addition of a double bond in the imidazoline to give an imidazole results in a decrease in potency and the introduction of benzylic hydroxyl group also reduces its activity by 4- and 6-fold, respectively. 2-Fluoro and 5-fluoro catecholimidazoline possess full agonist activity; their potencies being even higher than the parent molecule. The 6-fluoro analog is a partial agonist inasmuch as it produces a response that is only 30% of the maximum response produced by other analogs of imidazoline. In the present study, 4-substituted imidazolines retain their agonist activity, although weaker than desoxycatecholimidazoline. The potency of R- and S-isomers of 4-substituted catecholbenzyl imidazoline were similar. Although these isomers exhibit apparent chemical similarity to catecholamines, small differences between the activity of stereoisomers indicate that the mode of interaction of these molecules at alpha adrenoreceptor may differ from that of stereoisomers of epinephrine.     

Pharmacological properties of novel bicyclic isoquinoline analogs in isolated guinea pig atria, trachea and in human platelets: relationship to trimetoquinol.

1. Antiplatelet and beta-adrenoceptor activities of a set of secondary and tertiary N-methyl substituted amine analogs of trimetoquinol (TMQ, I and II, respectively) and 5,8-ethano-l-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquin oline (bicyclic isoquinoline compounds III and IV, respectively) were examined. 2. Compounds III and IV induced relaxations of guinea pig trachea which were blocked by propranolol whereas neither compound acted as an agonist nor antagonist of beta-adrenoceptors (chronotropy) in guinea pig atria. TMQ analogs (I and II) were agonists in both beta-adrenoceptor systems. 3. When tested in human platelets, compounds III and IV, like the TMQ analogs, blocked several inducers of the prostaglandin-dependent and -independent pathways, and the alpha 2-adrenoceptor-mediated pathway of platelet activation. 4. The bicyclic isoquinoline analogs (III and IV) possessed more selective beta 2-adrenoceptor stimulatory activity and equal or greater inhibitory activity against inducers of the prostaglandin-independent pathways of platelet function than the corresponding TMQ analogs (I and II). 5. These chemically novel lipophilic bicyclic compounds provide a new lead to the development of agents useful for the treatment of asthma and thrombotic disorders.     

Synthesis and β-Adrenergic Activities of R-Fluoronaphthyloxypropanolamine

Purpose. Many biogenic amines where an aromatic proton is substituted with fluorine have exhibited pharmacological properties that are dependent on the position of fluorine on the aromatic ring. For example, 6-fluoroepinephrine is selective for -adrenergic receptors whereas the 2-fluoroisomer is selective for -receptors. Aryloxypropanolamines are -receptor agonists or antagonists, depending on the aryl group and its substituents. We therefore hypothesized that fluorine substitution on the aromatic ring could lead to significant biological effects in this class. A target with fluorine on naphthyl group of a known -antagonist was chosen for investigation. Methods. Synthesis of the target compound began with fluoronaphthalene and involved introduction of 4-hydroxy group by Friedel-Crafts acylation followed by Baeyer Villiger oxidation. The side chain was introduced stereoselectively using the chiral synthon (2R)-glycidyl 3-nitrobenzenesulfonate, a Sharpless epoxidation technique. The epoxide was opened with t-butyl amine. HPLC methods were used to characterize %ee of the enantiomer. Results. The target compound was synthesized in several hundred milligram quantity, and in good yield and high enantiomeric excess, showing practicality of the synthetic scheme. It exhibited potent binding activities on -adrenergic receptors, and was found to be two times selective for ₂-receptors over ₁. Conclusions. The current report demonstrates that aromatic fluorine substitution on -adrenergic ligands can be achieved, and that such can be used to obtain binding selectivity between receptors.     

Syntheses and beta-adrenergic agonist and antiaggregatory properties of N-substituted trimetoquinol analogues

Trimetoquinol [1-(3,4,5-trimethoxybenzyl)-6,7- dihydroxy-1,2,3,4-tetrahydroisoquinoline, TMQ] is a potent beta-adrenergic receptor agonist and inhibitor of human platelet aggregation. Selective cleavage of O-benzyl groups in the presence of an N-benzyl group using HCl and formation of a cyclic sulfite ester from the reaction of a catechol with thionyl chloride were achieved. The N-substituents included methyl, benzyl, and beta-hydroxy- and beta-chloroethyl groups. Each N-substituted TMQ caused a concentration-dependent stimulation of beta 2 (trachea) and beta 1 (atria) adrenoceptor tissues and inhibition of 15(S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13(E)-dienoic acid (U46619, a thromboxane A2 mimetic) mediated human platelet activation. TMQ remained the most potent in the series. Structure-activity results indicated that the larger the N-substituent, the lower the beta-adrenergic activity but the higher the inhibition of platelet aggregatory activity. Thus, the structural requirements of these TMQ analogues for the two types of biological activity are different.     

Prevalence of postnatal depression in Western Nigerian women: a controlled study

Objective The objective of this study is to compare the prevalence of depression in postpartum women and that of non-postpartum women. Method A total of 876 women recruited at 6 weeks postpartum and 900 matched non-postpartum women were administered the Beck's Depressive Inventory (BDI) and translated local version of the EPDS. Psychiatric diagnosis was made using the using the modified non-patient version of Structured Clinical Interview for DSM-III-R (SCID-NP). Results Depressive disorder was diagnosed in 128 (14.6%) of the postpartum women and in 55 (6.3%) of the non-postpartum women, and the difference was found to be significant (t=8.919, df=875, P<0.001). The postpartum women had higher EPDS and BDI scores than the non-postpartum women. The EPDS correlated well with the SCID-NP diagnosis with a Spearman's correlation of 0.600 (P<0.001) and with the BDI score with a Spearman's correlation of 0.461 (P<0.001). The sensitivity of the EPDS at cut-off score of 8/9 was 94% and specificity was 97%. Conclusion The prevalence of postnatal depression in Nigeria is comparable to that of the western world and the Yoruba version of EPDS is a valid instrument for screening postnatal women for depressive disorders in a Nigerian community.     

Effect of aromatic fluorine substitution on the alpha and beta adrenoceptor-mediated effects of 3,4-dihydroxytolazoline in the pithed rat

The alpha and beta adrenoceptor-mediated effects of the catecholimidazoline, 3,4-dihydroxytolazoline, and its 2-, 5- and 6-aromatic fluorine-substituted derivatives have been studied in the cardiovascular system of the pithed rat. All four compounds produced vasopressor responses in beta adrenoceptor blocked (propranolol, 3 mg/kg i.v.) animals. The pressor responses produced by all four compounds were antagonized by the selective alpha-1 adrenoceptor antagonist, prazosin (0.1 mg/kg i.v.), and were relatively unaffected by the selective alpha-2 adrenoceptor antagonist, rauwolscine (0.5 mg/kg i.v.), indicating that vasoconstriction produced by the fluorinated imidazolines was mediated exclusively by postjunctional vascular alpha-1 adrenoceptors. The rank order of potency at the alpha-1 adrenoceptor was: 5-fluoro greater than 2-fluoro greater than desfluoro greater than 6-fluoro. At higher doses, 3,4-dihydroxytolazoline and its fluorinated derivatives produced an alpha-2 adrenoceptor-mediated inhibition of neurogenic tachycardia in animals pretreated with prazosin, with all four compounds being equipotent. In rats with complete alpha adrenoceptor blockade [phenoxybenzamine (3 mg/kg i.v.), prazosin (0.1 mg/kg i.v.) and rauwolscine (1 mg/kg i.v.)] whose blood pressure was elevated by constant infusion of angiotensin II (150 ng/kg/min i.v.), high doses of the 2-fluoro-, but not the 5-, 6- or desfluoro catecholimidazoline derivatives, produced a beta-2 adrenoceptor-mediated vasodepressor response. All four compounds produced a beta-1 adrenoceptor-mediated positive chronotropic response in pithed rats with the rank order of potency being: 2-fluoro = 5-fluoro greater than desfluoro greater than 6-fluoro.(ABSTRACT TRUNCATED AT 250 WORDS)