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result sql = In vivo and in vitro pharmacological characterization of SVT-40776, a novel M3 muscarinic receptor antagonist, for the treatment of overactive bladder.

In vivo and in vitro pharmacological characterization of SVT-40776, a novel M3 muscarinic receptor antagonist, for the treatment of overactive bladder.

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char = o;code = 111
char = n;code = 110
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = r;code = 114
char = b;code = 98
char = a;code = 97
char = c;code = 99
char = h;code = 104
char = o;code = 111
char = l;code = 108
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = u;code = 117
char = d;code = 100
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = f;code = 102
char = u;code = 117
char = n;code = 110
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = S;code = 83
char = V;code = 86
char = T;code = 84
char = -;code = 45
char = 4;code = 52
char = 0;code = 48
char = 7;code = 55
char = 7;code = 55
char = 6;code = 54
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = v;code = 118
char = i;code = 105
char = v;code = 118
char = o;code = 111
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = c;code = 99
char = y;code = 121
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = S;code = 83
char = V;code = 86
char = T;code = 84
char = -;code = 45
char = 4;code = 52
char = 0;code = 48
char = 7;code = 55
char = 7;code = 55
char = 6;code = 54
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = c;code = 99
char = h;code = 104
char = a;code = 97
char = r;code = 114
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = i;code = 105
char = z;code = 122
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = p;code = 112
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = o;code = 111
char = v;code = 118
char = o;code = 111
char = l;code = 108
char = u;code = 117
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = r;code = 114
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = s;code = 115
char = p;code = 112
char = o;code = 111
char = n;code = 110
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = e;code = 101
char = o;code = 111
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = b;code = 98
char = l;code = 108
char = a;code = 97
char = d;code = 100
char = d;code = 100
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = a;code = 97
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = z;code = 122
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = g;code = 103
char = u;code = 117
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = a;code = 97
char = ;code = 32
char = p;code = 112
char = i;code = 105
char = g;code = 103
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = f;code = 102
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = v;code = 118
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = d;code = 100
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = .;code = 46
char = ;code = 32
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = >;code = 62
char = K;code = 75
char = E;code = 69
char = Y;code = 89
char = ;code = 32
char = R;code = 82
char = E;code = 69
char = S;code = 83
char = U;code = 85
char = L;code = 76
char = T;code = 84
char = S;code = 83
char = :;code = 58
char = ;code = 32
char = <;code = 60
char = /;code = 47
char = b;code = 98
char = >;code = 62
char = ;code = 32
char = S;code = 83
char = V;code = 86
char = T;code = 84
char = -;code = 45
char = 4;code = 52
char = 0;code = 48
char = 7;code = 55
char = 7;code = 55
char = 6;code = 54
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = s;code = 115
char = t;code = 116
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = h;code = 104
char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = r;code = 114
char = b;code = 98
char = a;code = 97
char = c;code = 99
char = h;code = 104
char = o;code = 111
char = l;code = 108
char = -;code = 45
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = u;code = 117
char = c;code = 99
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = l;code = 108
char = a;code = 97
char = d;code = 100
char = d;code = 100
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = i;code = 105
char = -;code = 45
char = c;code = 99
char = h;code = 104
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = r;code = 114
char = g;code = 103
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ,;code = 44
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = o;code = 111
char = u;code = 117
char = t;code = 116
char = ;code = 32
char = a;code = 97
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = r;code = 114
char = i;code = 105
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = s;code = 115
char = a;code = 97
char = m;code = 109
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = a;code = 97
char = n;code = 110
char = g;code = 103
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = S;code = 83
char = V;code = 86
char = T;code = 84
char = -;code = 45
char = 4;code = 52
char = 0;code = 48
char = 7;code = 55
char = 7;code = 55
char = 6;code = 54
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = h;code = 104
char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = h;code = 104
char = i;code = 105
char = g;code = 103
char = h;code = 104
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = ;code = 32
char = u;code = 117
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = a;code = 97
char = r;code = 114
char = y;code = 121
char = ;code = 32
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = s;code = 115
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = r;code = 114
char = d;code = 100
char = i;code = 105
char = a;code = 97
char = c;code = 99
char = ;code = 32
char = s;code = 115
char = e;code = 101
char = l;code = 108
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = ;code = 32
char = (;code = 40
char = 1;code = 49
char = 9;code = 57
char = 9;code = 57
char = -;code = 45
char = f;code = 102
char = o;code = 111
char = l;code = 108
char = d;code = 100
char = );code = 41
char = .;code = 46
char = ;code = 32
char = I;code = 73
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = g;code = 103
char = u;code = 117
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = a;code = 97
char = ;code = 32
char = p;code = 112
char = i;code = 105
char = g;code = 103
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = v;code = 118
char = i;code = 105
char = v;code = 118
char = o;code = 111
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = ,;code = 44
char = ;code = 32
char = S;code = 83
char = V;code = 86
char = T;code = 84
char = -;code = 45
char = 4;code = 52
char = 0;code = 48
char = 7;code = 55
char = 7;code = 55
char = 6;code = 54
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = h;code = 104
char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = 2;code = 50
char = 5;code = 53
char = %;code = 37
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = s;code = 115
char = p;code = 112
char = o;code = 111
char = n;code = 110
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = e;code = 101
char = o;code = 111
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = b;code = 98
char = l;code = 108
char = a;code = 97
char = d;code = 100
char = d;code = 100
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = y;code = 121
char = ;code = 32
char = l;code = 108
char = o;code = 111
char = w;code = 119
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = 6;code = 54
char = .;code = 46
char = 9;code = 57
char = 7;code = 55
char = ;code = 32
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = r;code = 114
char = o;code = 111
char = g;code = 103
char = .;code = 46
char = k;code = 107
char = g;code = 103
char = (;code = 40
char = -;code = 45
char = 1;code = 49
char = );code = 41
char = ;code = 32
char = i;code = 105
char = .;code = 46
char = v;code = 118
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = o;code = 111
char = u;code = 117
char = t;code = 116
char = ;code = 32
char = a;code = 97
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = i;code = 105
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = b;code = 98
char = l;code = 108
char = o;code = 111
char = o;code = 111
char = d;code = 100
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = .;code = 46
char = ;code = 32
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = >;code = 62
char = C;code = 67
char = O;code = 79
char = N;code = 78
char = C;code = 67
char = L;code = 76
char = U;code = 85
char = S;code = 83
char = I;code = 73
char = O;code = 79
char = N;code = 78
char = S;code = 83
char = ;code = 32
char = A;code = 65
char = N;code = 78
char = D;code = 68
char = ;code = 32
char = I;code = 73
char = M;code = 77
char = P;code = 80
char = L;code = 76
char = I;code = 73
char = C;code = 67
char = A;code = 65
char = T;code = 84
char = I;code = 73
char = O;code = 79
char = N;code = 78
char = S;code = 83
char = :;code = 58
char = ;code = 32
char = <;code = 60
char = /;code = 47
char = b;code = 98
char = >;code = 62
char = ;code = 32
char = S;code = 83
char = V;code = 86
char = T;code = 84
char = -;code = 45
char = 4;code = 52
char = 0;code = 48
char = 7;code = 55
char = 7;code = 55
char = 6;code = 54
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = h;code = 104
char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = M;code = 77
char = (;code = 40
char = 3;code = 51
char = );code = 41
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = c;code = 99
char = e;code = 101
char = p;code = 112
char = t;code = 116
char = o;code = 111
char = r;code = 114
char = -;code = 45
char = r;code = 114
char = e;code = 101
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = t;code = 116
char = r;code = 114
char = u;code = 117
char = s;code = 115
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = l;code = 108
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = b;code = 98
char = s;code = 115
char = e;code = 101
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = s;code = 115
char = o;code = 111
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = r;code = 114
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result sql = BACKGROUND AND PURPOSE: Highly selective M(3) muscarinic receptor antagonists may represent a better treatment for overactive bladder syndrome, diminishing side effects. Cardiac side effects of non-selective antimuscarinics have been associated with activity at M(2) receptors as these receptors are mainly responsible for muscarinic receptor-dependent bradycardia. We have investigated a novel antimuscarinic, SVT-40776, highly selective for M(3) over M(2) receptors (Ki = 0.19 nmol.L(-1) for M(3) receptor affinity). This study reports the functional activity of SVT-40776 in the bladder, relative to its activity in atria.

EXPERIMENTAL APPROACH: In vitro and ex vivo (oral dosing) inhibition of mouse detrusor and atrial contractile responses to carbachol were used to study the functional activity of SVT-40776. The in vivo efficacy of SVT-40776 was characterized by suppression of isovolumetric spontaneous bladder contractions in anaesthetized guinea pigs after intravenous administration.

KEY RESULTS: SVT-40776 was the most potent in inhibiting carbachol-induced bladder contractions of the anti-cholinergic agents tested, without affecting atrial contractions over the same range of concentrations. SVT-40776 exhibited the highest urinary versus cardiac selectivity (199-fold). In the guinea pig in vivo model, SVT-40776 inhibited 25% of spontaneous bladder contractions at a very low dose (6.97 microg.kg(-1) i.v), without affecting arterial blood pressure.

CONCLUSIONS AND IMPLICATIONS: SVT-40776 is a potent inhibitor of M(3) receptor-related detrusor contractile activity. The absence of effects on isolated atria preparations represents an interesting characteristic and suggests that SVT-40776 may lack unwanted cardiac effects; a feature especially relevant in a compound intended to treat mainly elderly patients.

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