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P N Patil

Publications and source records attributed to P N Patil.

At least 19 recordsLinked to original sources
PubMed1996

Medetomidine analogs as alpha 2-adrenergic ligands. 2. Design, synthesis, and biological activity of conformationally restricted naphthalene derivatives of medetomidine.

A new series of naphthalene analogs of medetomidine have been prepared and evaluated for their alpha-adrenergic activities. The methylnaphthyl analog 5a showed significant selectivity for alpha 2-adrenoceptors and behaved as a partial alpha 1-agonist in rat aorta preparations. In contrast, the Z-ethylene analog 8c was alpha 1-selective and behaved as a potent alpha 1-antagonist. Two rigid analogs (6 and 7) exhibited large differences in binding affinities at alpha 1-VS alpha 2-receptors, indicating that the conformational flexibility of 5a is important for the fulfillment of the alpha-adrenergic activities. Molecular modeling studies began with conformational analysis of classical phenethylamines and medetomidine analogs. Superimposition of medetomidine conformations with those of phenethylamines provided a tentative explanation for the alpha 2-adrenergic activity of the new imidazoles. A common binding mode for phenethylamines and imidazoles with alpha 2-adrenoceptors is proposed. Knowledge of the biological properties of the 4-substituted imidazoles, integrated with the information derived from computer-assisted molecular modeling, has provided new insights for the structural and conformational requirements of this class as new adrenergic drugs.

Adrenergic alpha-Agonists↗
PubMed1996

Stereoselective modification of circular dichroism spectra of rat lung beta-adrenoceptor protein preparation by enantiomers of epinephrine.

The presence of beta-adrenoceptor in a rat lung membrane preparation was confirmed by stereoselective competition of enantiomers of epinephrine with labeled iodocyanopindolol. The receptor-rich protein fraction, when combined with the pharmacologically active (-)-epinephrine, exhibited specific changes in the 205-220 nm region of circular dichroism spectra, indicating that the receptor helices may be perturbed. The (+)-epinephrine combined with the lung protein produced little or no change of the spectra. Bovine serum albumin, when combined with either enantiomer of epinephrine, produced nonstereoselective alterations of the spectra. Thus, the data provide important evidence for the higher intrinsic pharmacologic activity of the natural (-)-epinephrine over the unnatural (+)-enantiomer.

Adrenergic beta-Antagonists↗
PubMed1996

Comparison of post-junctional alpha-adrenoceptors in iris dilator muscle of humans, and albino and pigmented rabbits.

The relative potency of alpha-adrenoceptor agonists and the dissociation constants of competitive antagonists were studied to characterize the post-junctional alpha-adrenoceptor of the human iris dilator muscle. The data obtained from human iris dilator tissue was compared to that from rabbit. The iris dilator muscle was mounted in an organ bath and tension changes were recorded. (-)-Norepinephrine, (-)-phenylephrine (PE), oxymetazoline and p-aminoclonidine caused contractile responses in albino rabbit, pigmented rabbit and human iris dilator muscle in a concentration-dependent manner. The imidazoline molecules were partial agonists. In rabbit iris dilator, desensitization occurred to repeated oxymetazoline application at an interval of 1 h but recovery to the agonist activity was complete in about 3 h. Exposure to cocaine (10 mumol/l), hydrocortisone (100 mumol/l) and U-0521, a catechol-O-methyltransferase inhibitor (100 mumol/l), significantly potentiated the response to norepinephrine by 92-, 32- and 7 fold in iris dilator tissue of albino rabbit, pigmented rabbit and human, respectively. After block of "uptake1" and "uptake2", the EC50 values of norepinephrine in the albino rabbit, pigmented rabbit and human iris dilator did not differ and ranged from 99 to 195 nmol/l. Small but significant potentiation by uptake blockers was also observed in the responses to PE in the albino rabbit or pigmented rabbit iris dilator. The average maximum tension induced by 100 mumol/l PE was 96 +/- 11 mg (n = 10), 197 +/- 11 mg (n = 11), 45 +/- 5 mg (n = 27) in albino rabbit, pigmented rabbit and human iris dilator, respectively. In human iris dilator, the responses to PE were competitively antagonized by prazosin, 5-methylurapidil and phentolamine with apparent pKB values of 7.3, 6.6 and 7.5, respectively. The pKB values of the prazosin-PE interaction in iris dilator of albino and pigmented rabbit were 8.6 and 6.4, respectively. These results suggest that the post-junctional alpha-adrenoceptors in iris dilator may be similar to that in pigmented rabbit iris. The alpha-adrenoceptor of the human or pigmented rabbit iris dilator may be characterized as alpha 1L-adrenoceptor subtype. The alpha-adrenoceptor of albino rabbit iris dilator appears to be a high affinity subtype. Furthermore, albino rabbit may not be the best strain for the drug research which is relevant to human ocular therapeutics.

Adult↗
PubMed1996

Actions of imidazolines on bovine ciliary artery.

A segment of bovine ciliary artery exhibits nonlinear biphasic contractile responses to agonists. The maximal responses of oxymetazoline (OMZ) and norepinephrine (NE) were 55% and 45%, respectively (KCl = 100%). The relative potency comparison based on the ED50 of the first component of the dose-response curve was OMZ; 1 > NE; 1/7 > phenylephrine; 1/72. At equipotent doses of NE and OMZ, the t1/2 duration of response of the latter agonist was 43 times greater than that of the former and, after 3 hrs, responses were 95% reproducible. Naphazoline, tetrahydrozoline and para-aminoclonidine did not produce significant contraction of the blood vessel but did antagonize the action of the agonists. As compared to that of NE, naphazoline was selective in blocking responses of OMZ. Phentolamine blocking action of NE was greater than that of OMZ. Nifedipine, 100 nM, reduced the second component of OMZ response. Although the vascular action of NE was blocked by prazosin, the contractile action of OMZ was totally resistant to block by 1 microM of prazosin. These results indicate that ciliary artery contains a subtype of alpha-adrenoceptors (alpha 11) with low sensitivity to prazosin. The tissue also contains a unique OMZ sensitive site or imidazoline receptors which exhibit low affinity to alpha-adrenoceptor blockers.

Adrenergic alpha-Agonists↗
PubMed1996

Pharmacologic quantitation.

Either in vivo or in vitro quantitatives comparisons of drugs based on the dose-response relations were known for a long time. For therapeutically targeted molecular structure activity studies, agonists are simply compared on the basis of concentrations eliciting half-maximum response (EC50) and per cent maximum response elicited by drugs in the given system. For partial agonists the receptor affinity determined as the dissociation constant (KA) in homogenates corresponds to that in the organ system. However, due to the presence of spare receptors the EC50 of potent agonists does not represent the KA. If a fraction of receptors are irreversibly inactivated in the tissue, KA as well as relative intrinsic efficacy of the potent agonists can be obtained. Although quantitation of irreversible antagonists is quite complex, the competitive reversible blockers can be accurately compared on the basis of equilibrium dissociation constant (KB) values. Along with the relative order of potency of agonists and KB values of antagonists, receptors can be characterized and subclassified. Preclinical Therapeutic Index of drugs and Toxicity Index of pesticides require determinations of mean lethal dose (LD50) and the mean effective dose (ED50) in laboratory animals, so that a relatively safe drug can be promoted for human use. The understanding of pharmacokinetics is essential to explain drug action in the target organs. Drug combinations are investigated by isobolorographic analysis.

Animals↗
PubMed1995

Infectivity of algal viruses studied by chlorophyll fluorescence.

Algal virus infection proceeds via the specific recognition of the host cell wall, penetration of the cell wall and transfer of genetic material into the cytoplasm of the host cell. This process is similar to that which occurs when bacteriophage infect bacteria so that techniques and concepts developed to study bacteriophage are applicable to algal virus studies. By measuring virus-induced changes in chlorophyll fluorescence we have redefined classical studies on the distribution of infectivity. We show that infectivity does not follow a Poisson distribution with a fixed mean, n. By analysing the infectivity of algal viruses over a broad range of virus:cell ratios we have obtained a corrected Poisson distribution that reflects the probability of multiple virus particles attached per cell and is equally applicable to algal viruses and bacteriophage.

Chlorella↗
PubMed1994

Synthesis and biological activities of a new set of irreversibly acting 2-(4'-isothiocyanatobenzyl)imidazoline analogs in rat thoracic aorta.

IBI [2-(4'-isothiocyanatobenzyl)imidazoline, 3] has been shown to cause slow-onset, long-lasting contractions of rat thoracic aorta through a non-alpha-adrenergic receptor (non-alpha-AR) mediated mechanism. A series of IBI-related anlogs 7-14 and 16 was prepared to determine the structural requirements for the interaction with non-alpha-AR in rat aortic strips. All IBI analogs produced concentration-dependent contractile responses on rat thoracic aorta. Whereas the actions of analogs 7, 14, and 16 were partly mediated by alpha-ARs, the stimulatory activities of the remaining IBI analogs were unaffected by phenoxybenzamine pretreatment, suggesting that a non-alpha-adrenergic mechanism is involved. We have shown that the contractile actions of IBI and analogs 10-13 were not blocked with the imidazoline/guanidinium receptive site (IGRS) ligands idazoxan, cirazoline, or clonidine. However, the calcium channel blockers nifedipine or verapamil shifted the concentration-response curve of IBI and its analogs 10-13 to the right and reduced the maximal contractile responses. The action of IBI on rat thoracic aorta was reduced by the omission of extracellular calcium in the medium. These results suggest that the stimulatory activities of IBI and analogs 10-13 are not related to the activation of alpha-AR or IGRS receptors and are likely coupled to the voltage-dependent Ca2+ channels.

Animals↗
PubMed1994

Relevance of drug-melanin interactions to ocular pharmacology and toxicology.

In melanocytes, the biosynthesis of L-dopa derived indole polymer, melanin, is accelerated by tyrosinase and related enzymes. The brown to black pigment is characterized by a stable free-radical property. In humans, a pigment dependent slow onset of ocular actions of ephedrine, atropine, cocaine, pilocarpine and related medications was observed. Extensive accumulation of drugs by melanin appears to be the most important factor governing the long term therapeutic/toxicological activities. Drugs crossing placental circulation are localized in the mouse fetal eye. Thus, drugs exhibit a high binding capacity for melanin containing tissues. Studies on synthetic melanin and melanin granules also indicated a high binding capacity of many therapeutic classes of drugs, including psychotropics. In addition to the liposoluble property of the molecule, there is a definite relationship between chemical structure and the affinity of drugs for melanin. For example, the affinity of chlorpromazine for melanin is higher than that of chlorprothixene. NMR studies, with soluble melanins indicate that there is a steric preference among ephedrine enantiomers. A high binding capacity indicates that more than two molecules of (-)-ephedrine may complex with one indole unit of melanin. Ocular drug development calls for the study of qualitative and quantitative aspects of drug-melanin interaction.

Animals↗
PubMed1992

Synthesis and alpha-adrenergic activities of 2- and 4-substituted imidazoline and imidazole analogues.

Seven analogues of medetomidine and naphazoline were synthesized and evaluated for their alpha 1 (aorta) and alpha 2 (platelet) activities. The analogues were composed of 2- and 4-substituted imidazoles and imidazolines attached through a methylene bridge to either the 1- or 2-naphthalene ring system. In general the 1-naphthalene analogues were the most potent inhibitors of epinephrine-induced platelet aggregation. Of considerable interest was the fact that the 1-naphthalene analogues (2, 5-7) were partial agonists while the 2-naphthalene analogues (3, 8, 9) were antagonists in an alpha 1-adrenergic system (aorta). Thus, appropriately substituted naphthalene analogues of medetomidine and naphthazoline provide a spectrum of alpha 1-agonist, alpha 1-antagonist, and alpha 2-antagonist activity.

Adrenergic alpha-Agonists↗
PubMed1992

Reactivity of human iris-sphincter to muscarinic drugs in vitro.

From tissue to tissue the contractile response of human irides to carbachol varied by 40 fold. The mean EC50 value of carbachol in tissues remaining in an in vitro environment for 24-37 h was equal, however, to that obtained from tissues examined during 79-161 h. The maximum response of the tissue to the highest concentration of carbachol increased up to 24 h, then a gradual decline in the maximum occurred. In 38 observations, the average decline after 72 h was approximately 30%. A plot of negative log EC50 values (n = 38) of carbachol exhibited normal Gaussian curve. The geometric mean EC50 value of carbachol was 0.38 mumol/l (0.28-0.51 mumol/l, 95% C.L.). Based on EC50 values, the rank order of potency of cholinergic agonists is as follows: Muscarine = carbachol, 1 > pilocarpine, 1/5 > methacholine, 1/23 > bethanechol, 1/29 > acetylcholine, 1/1310. The percent maximum contraction of irides to muscarine, carbachol, pilocarpine, methacholine and bethanechol were 100, 100, 80, 76 and 95, respectively. Acetylcholine at the highest concentration tested produced 71% of the maximum produced by carbachol. Within a concentration range of 1 to 100 mumol/l, physostigmine consistently contracted isolated irides. The mean EC50 value was 6.73 mumol/l. The effect was sensitive to blockade by atropine. When the temperature of the bathing medium was lowered from 37.5 degrees C to 27.5 degrees C or 17.5 degrees C the magnitude and the duration of the response of the iris to carbachol was increased, the EC50 value, however, was not changed significantly. The response to pilocarpine was similarly altered by the lower temperature.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Cholinergic sensitivity of irides from donors with various pathological conditions and lens implants.

In vitro, iris contractions after muscarinic agonists were measured in mg of tension change and the concentration producing 50% of the response was expressed as EC50 mumol/l. Although the average EC50 value of carbachol in the iris sphincter of the donors with diabetes or Parkinson's disease did not change significantly when compared with the control, the maximum contraction of the tissue from the diseased state was increased significantly. Thus, in addition to the well known denervation supersensitivity of the iris-dilator, the iris-sphincter also develops adaptive sensitivity changes. Antimuscarinic drug treatment in some Parkinson's patients interfered with the estimation of supersensitivity in vitro studies. The enhanced response of carbachol at the low temperatures or the relative potency of carbachol and pilocarpine in the tissue obtained from the diseased donors was not significantly different from that of controls. Based on EC50 values, the potency of arecoline on the iris was 1/3 that of carbachol. Significantly lower EC50 values of carbachol were found in irides which were in contact with open loop type anterior chamber lens implants compared with those in contact with the closed loop anterior chamber lens implants. Maximum responses of irides to carbachol were less when the tissue was in contact with open loop lens compared with those in contact with closed loop anterior chamber implants. Irides from many donors having unilateral or bilateral replacement of the artificial lenses responded with EC50 of carbachol which was approximately equal to that of the contralateral eye. The maximum difference between EC50 values of the left and right iris was less than 5 fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Diversity of the pharmacological actions of some tolazoline analogues in human platelets and rat aorta.

Tolazoline and two 4'-substituted benzyl analogues, 2-(4'-aminobenzyl) imidazoline (ABI) and 2-(4'-isothiocyanatobenzyl)imidazoline (IBI) were synthesized and evaluated for adrenoceptor activity in human platelets (alpha 2) and rat aorta (alpha 1), respectively. IBI was prepared as an affinity label for alpha-adrenoceptors and compared with chloroethylclonidine. Tolazoline, IBI, ABI and chloroethylclonidine inhibited the primary and secondary waves of epinephrine-induced human platelet aggregation. In aspirin treated platelets, primary wave aggregatory responses to epinephrine were blocked in a competitive manner by tolazoline, ABI. IBI and chloroethylclonidine giving pA2 values of 6.33, 6.12, 4.71 and 5.70, respectively. Only IBI blocked the aggregation responses to ADP (secondary wave only) arachidonic acid and U46619 (a thromboxane A2 agonist). Arachidonic acid-induced serotonin release and malondialdehyde formation and thrombin-induced release of [3H]arachidonic acid from membrane phospholipids were also blocked by IBI. These data indicate that IBI blocks arachidonic acid release, prostaglandin biosynthesis and the action of thromboxane A2. One hour exposure of aspirin treated platelets with IBI abolished inhibitory effects against epinephrine induced aggregation. In contrast to human platelets, both ABI and IBI produced contractions of rat aorta; however, only the responses to ABI were blocked in a competitive manner by the alpha-antagonists, phentolamine, prazosin, and SKF 104078. Moreover, idazoxan blocked the stimulatory actions of IBI, cirazoline and phenylephrine on rat aorta.(ABSTRACT TRUNCATED AT 250 WORDS)

Affinity Labels↗
PubMed1991

Pharmacologic antagonism of thromboxane A2 receptors by trimetoquinol analogs in vitro and in vivo.

Although (-)-(S)-trimetoquinol [1-(3,4,5-trimethoxy-benzyl)- 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline; TMQ] is recognized as a potent bronchodilator, (+)-(R)-TMQ is a selective antagonist of human platelet aggregation and serotonin secretion induced by thromboxane A2 (TXA2) agonists. To confirm the pharmacological actions of TMQ analogs, the interaction of the drugs with TXA2 receptors was examined in human platelets and in a mouse sudden death model. The inhibitory potencies of TMQ analogs (pIC50 values) for displacement of [3H]SQ 29,548 binding to platelets showed excellent correlation with the respective pIC50 (-log IC50) values for U46619-induced aggregation (r = 0.99, P less than 0.01) and serotonin secretion (r = 0.99, P less than 0.01) in human platelet-rich plasma and for whole blood aggregation (r = 0.99, P less than 0.01). In each system, the rank order of inhibitory potencies was rac-iodoTMQ greater than or equal to (+)-(R)-TMQ greater than rac-TMQ much greater than (-)-(S)-TMQ. Antithrombotic effects of TMQ analogs were evaluated in a mouse sudden death model. In vivo antithrombotic potencies of these compounds were consistent with the in vitro potencies as TXA2 receptor antagonists in platelet systems. Administration of rac-iodoTMQ, (+)-(R)-TMQ and rac-TMQ 15 min before the injection of U46619 (800 micrograms/kg, iv) protected mice against U46619-induced sudden death. On the other hand, (-)-(S)-TMQ did not protect animals against death. Protection of U46619-induced cardiopulmonary thrombosis by TMQ analogs was seen at doses of 3-100 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Molecular aspects of the receptor activation by imidazolines: an overview.

Based on the pharmacological activity of chiral imidazolines the steric requirements for the activation of the alpha-adrenoceptor are provided. Importantly, the sequence of interaction of the critical groups of the asymmetric carbon of imidazolines and catecholamines with the alpha-adrenoceptor is postulated. Thus, initial determinants of molecular efficacy are hypothesized. The effect of aromatic fluoro-substitution and introduction of a double bond in the imidazoline moiety on the pharmacologic activity is discussed. The unique mechanism of non-adrenergic vascular activity of isothiocyanato-tolazoline is presented.

Animals↗
PubMed1991

In vivo functional implications of isoproterenol-mediated relaxation of isolated human iris sphincter.

The isolated human iris sphincter contracted with carbachol produced relaxation with an average ED50 of 1.30 x 10(-7) M for (-)-isoproterenol. The effect is sensitive to block by (-)-timolol with KB 3 x 10(-9) M. The magnitude of the average relaxation mediated by the beta-adrenoceptor agonist was only 31%. Lowering of the temperature did not potentiate the effect of (-)-isoproterenol to a significant extent. Thus, in contrast to bovine iris sphincter, where the beta-adrenoceptor mediated response of (-)-isoproterenol produces a maximum relaxation or complete mydriasis, the maximum beta-adrenoceptor mediated mydriasis of human iris may not be more than 1/3 of the maximum pupillary dilatation achieved by physiologic or pharmacologic procedures.

Aged↗
PubMed1990

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.

Blood Platelets↗
PubMed1989

Pharmacologic implications of alpha-adrenoreceptor interactive parameters for epinephrine enantiomers in the rat vas deferens.

After alkylation of a fraction of the total alpha-adrenoreceptors by phenoxybenzamine in rat vas deferens, the dissociation constants of (-)- and (+)-epinephrine in functional studies were 7 X 10(-7) M and 2 X 10(-5) M, respectively. In the adrenoreceptor-containing tissue fraction, when 3H-labeled WB4101 was used as the interacting ligand, for each enantiomer two affinity sites were found. Only the low-affinity dissociation constant for each isomer correlates with the constant obtained from the functional studies. If the change in Gibb's free energy, delta G degrees, is calculated from the low-affinity binding constants, the values -8.1 and -6.2 kcal/mol for (-)- and (+)-isomer, respectively, are obtained. The small difference in the value between isomers is consistent with the view that the benzylic hydroxyl group of the (-)-isomer forms a hydrogen bond with the receptor. The interaction of epinephrine with this receptor appears to be driven largely by the entropy of the drug-receptor interaction with only a small nonstereoselective contribution from the enthalpy of interaction.

Animals↗